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Professor Richard Houlston
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Johansson, M., Carreras-Torres, R., Scelo, G., Purdue, M.P., Mariosa, D., Muller, D.C., Timpson, N.J., Haycock, P.C., Brown, K.M., Wang, Z., et al. (2019). The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study. Plos med, Vol.16 (1), p. e1002724. show abstract
BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk..
Studd, J.B., Yang, M., Li, Z., Vijayakrishnan, J., Lu, Y., Yeoh, A.E., Paulsson, K. & Houlston, R.S. (2019). Genetic predisposition to B-cell acute lymphoblastic leukemia at 14q11 2 is mediated by a CEBPE promoter polymorphism. Leukemia, Vol.33 (1), pp. 1-14. show abstract
Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Genome-wide association studies have shown variation at 14q11.2 influences ALL risk. We sought to decipher causal variant(s) at 14q11.2 and the mechanism of tumorigenesis. We show rs2239630 G>A resides in the promoter of the CCAT enhancer-binding protein epsilon (CEBPE) gene. The rs2239630-A risk allele is associated with increased promotor activity and CEBPE expression. Depletion of CEBPE in ALL cells reduces cell growth, correspondingly CEBPE binds to the promoters of electron transport and energy generation genes. RNA-seq in CEBPE depleted cells demonstrates CEBPE regulates the expression of genes involved in B-cell development (IL7R), apoptosis (BCL2), and methotrexate resistance (RASS4L). CEBPE regulated genes significantly overlapped in CEBPE depleted cells, ALL blasts and IGH-CEBPE translocated ALL. This suggests CEBPE regulates a similar set of genes in each, consistent with a common biological mechanism of leukemogenesis for rs2239630 associated and CEBPE translocated ALL. Finally, we map IGH-CEBPE translocation breakpoints in two cases, implicating RAG recombinase activity in their formation..
Amirian, E.S., Ostrom, Q.T., Armstrong, G.N., Lai, R.K., Gu, X., Jacobs, D.I., Jalali, A., Claus, E.B., Barnholtz-Sloan, J.S., Il'yasova, D., et al. (2019). Aspirin, NSAIDs, and Glioma Risk: Original Data from the Glioma International Case-Control Study and a Meta-analysis. Cancer epidemiol biomarkers prev, Vol.28 (3), pp. 555-562. show abstract
BACKGROUND: There have been few studies of sufficient size to address the relationship between glioma risk and the use of aspirin or NSAIDs, and results have been conflicting. The purpose of this study was to examine the associations between glioma and aspirin/NSAID use, and to aggregate these findings with prior published studies using meta-analysis. METHODS: The Glioma International Case-Control Study (GICC) consists of 4,533 glioma cases and 4,171 controls recruited from 2010 to 2013. Interviews were conducted using a standardized questionnaire to obtain information on aspirin/NSAID use. We examined history of regular use for ≥6 months and duration-response. Restricted maximum likelihood meta-regression models were used to aggregate site-specific estimates, and to combine GICC estimates with previously published studies. RESULTS: A history of daily aspirin use for ≥6 months was associated with a 38% lower glioma risk, compared with not having a history of daily use [adjusted meta-OR = 0.62; 95% confidence interval (CI), 0.54-0.70]. There was a significant duration-response trend (P = 1.67 × 10-17), with lower ORs for increasing duration of aspirin use. Duration-response trends were not observed for NSAID use. In the meta-analysis aggregating GICC data with five previous studies, there was a marginally significant association between use of aspirin and glioma (mOR = 0.84; 95% CI, 0.70-1.02), but no association for NSAID use. CONCLUSIONS: Our study suggests that aspirin may be associated with a reduced risk of glioma. IMPACT: These results imply that aspirin use may be associated with decreased glioma risk. Further research examining the association between aspirin use and glioma risk is warranted..
Chattopadhyay, S., Zheng, G., Sud, A., Sundquist, K., Sundquist, J., Försti, A., Houlston, R., Hemminki, A. & Hemminki, K. (2019). Second primary cancers in non-Hodgkin lymphoma: Family history and survival. Int j cancer, . show abstract
Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses and family history of cancer may be a risk factor for SPCs. Using the Swedish Family-Cancer Database on non-Hodgkin lymphoma (NHL), we assessed the influence of family history on risk of SPCs and of SPCs on survival. NHL patients were identified from the years 1958 to 2015 and generalized Poisson models were used to calculate relative risks (RRs) for SPCs and familial SPCs. Among 14,393 NHL patients, a total of 1,866 (13.0%) were diagnosed with SPC. Familial risk of nine particular cancers was associated with risks of these cancers as SPCs, with twofold to fivefold increase in RRs. At the end of a 25-year follow-up period, the survival probability for persons with SPC was only 20% of that for patients without SPC; the hazard ratio for SPC was 1.59 (95% CI: 1.46-1.72). Survival could be predicted by the prognostic groups based on first cancers and HRs increase systematically with worse prognosis yielding a trend of p = 4.6 × 10-5 . SPCs had deleterious consequences for survival in NHL patients. Family history was associated with increasing numbers of SPCs. Prevention of SPCs and their early detection is an important target in the overall strategy to improve survival in NHL patients. Counseling for avoidance of risk factors and targeted screening based on family history are feasible steps in risk reduction..
Zheng, G., Chattopadhyay, S., Sud, A., Sundquist, K., Sundquist, J., Försti, A., Houlston, R., Hemminki, A. & Hemminki, K. (2019). Second primary cancers in patients with acute lymphoblastic, chronic lymphocytic and hairy cell leukaemia. Br j haematol, Vol.185 (2), pp. 232-239. show abstract
Improvement of survival in lymphocytic leukaemia has been accompanied by the occurrence of second primary cancer (SPCs). Based on Swedish Family Cancer Database, we applied bi-directional analyses in which relative risks (RRs) were calculated for any SPCs in patients with chronic lymphocytic leukaemia (CLL), acute lymphoblastic leukaemia (ALL) and hairy cell leukaemia (HCL) and the risks of these leukaemias as SPCs. After CLL, RRs were significant for 20 SPCs, and high for skin squamous cell cancer (24·58 for in situ and 7·63 for invasive), Merkel cell carcinoma (14·36), Hodgkin lymphoma (7·16) and Kaposi sarcoma (6·76). Conversely, 15 CLL cancer pairs were reciprocally increased. The increased risks were reciprocal for ALL and four cancers. RR for ALL was 15·35 after myeloid neoplasia. HCL showed reciprocally increased RRs with non-Hodgkin lymphoma and melanoma. The concordance between RRs for bi-directional associations between CLL and different cancers, and HCL and different cancers was highly significant. For CLL (also for HCL), the bi-directional risks with skin cancers and other immune-related cancers suggest the probable involvement of immune dysfunction. For ALL, treatment may contribute to risks of multiple SPCs. Increased risk of ALL after haematological neoplasms may indicate bone marrow dysfunction. These findings may help guide treatment decisions and prognostic assessment..
Zhu, Y., Wei, Y., Zhang, R., Dong, X., Shen, S., Zhao, Y., Bai, J., Albanes, D., Caporaso, N.E., Landi, M.T., et al. (2019). Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis. Cancer epidemiol biomarkers prev, Vol.28 (5), pp. 935-942. show abstract
BACKGROUND: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. METHODS: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. RESULTS: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non-small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. CONCLUSIONS: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. IMPACT: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention..
Went, M., Sud, A., Li, N., Johnson, D.C., Mitchell, J.S., Kaiser, M. & Houlston, R.S. (2019). Regions of homozygosity as risk factors for multiple myeloma. Ann hum genet, Vol.83 (4), pp. 231-238. show abstract
Genomic regions of homozygosity (ROH), detectable in outbred populations, have been implicated as determinants of inherited risk. To examine whether ROH is associated with risk of multiple myeloma (MM), we performed whole-genome homozygosity analysis using single-nucleotide polymorphism genotype data from 2,282 MM cases and 5,197 controls, with replication in an additional 878 MM cases and 7,083 controls. Globally, the distribution of ROH between cases and controls was not significantly different. However, one ROH at chromosome 9q21, harboring the B-cell transcription factor gene KLF9, showed evidence of a consistent association and may therefore warrant further investigation as a candidate risk factor for MM. Overall, our analysis provides little support for a homozygosity signature being a significant factor in MM risk..
Thomsen, H., Chattopadhyay, S., Weinhold, N., Vodicka, P., Vodickova, L., Hoffmann, P., Nöthen, M.M., Jöckel, K.-., Langer, C., Hajek, R., et al. (2019). Genome-wide association study of monoclonal gammopathy of unknown significance (MGUS): comparison with multiple myeloma. Leukemia, Vol.33 (7), pp. 1817-1821.
Cornish, A.J., Hoang, P.H., Dobbins, S.E., Law, P.J., Chubb, D., Orlando, G. & Houlston, R.S. (2019). Identification of recurrent noncoding mutations in B-cell lymphoma using capture Hi-C. Blood adv, Vol.3 (1), pp. 21-32. show abstract
The identification of driver mutations is fundamental to understanding oncogenesis. Although genes frequently mutated in B-cell lymphoma have been identified, the search for driver mutations has largely focused on the coding genome. Here we report an analysis of the noncoding genome using whole-genome sequencing data from 117 patients with B-cell lymphoma. Using promoter capture Hi-C data in naive B cells, we define cis-regulatory elements, which represent an enriched subset of the noncoding genome in which to search for driver mutations. Regulatory regions were identified whose mutation significantly alters gene expression, including copy number variation at cis-regulatory elements targeting CD69, IGLL5, and MMP14, and single nucleotide variants in a cis-regulatory element for TPRG1 We also show the commonality of pathways targeted by coding and noncoding mutations, exemplified by MMP14, which regulates Notch signaling, a pathway important in lymphomagenesis and whose expression is associated with patient survival. This study provides an enhanced understanding of lymphomagenesis and describes the advantages of using chromosome conformation capture to decipher noncoding mutations relevant to cancer biology..
Ostrom, Q.T., Egan, K.M., Nabors, L.B., Gerke, T., Thompson, R.C., Olson, J.J., LaRocca, R., Chowdhary, S., Eckel-Passow, J.E., Armstrong, G., et al. (2019). Glioma risk associated with extent of estimated European genetic ancestry in African Americans and Hispanics. Int j cancer, . show abstract
Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR≥0.4 ), and ≥15% NAA (AMR≥0.15 ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10-4 ; 11p11.12, p = 7.0 × 10-4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR≥0.4 . In addition, we identified a peak at rs1620291 (p = 4.36 × 10-6 ) in 7q21.3. Among AMR≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10-4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10-4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies..
Ofoegbu, T.C., David, A., Kelley, L.A., Mezulis, S., Islam, S.A., Mersmann, S.F., Strömich, L., Vakser, I.A., Houlston, R.S. & Sternberg, M.J., et al. (2019). PhyreRisk: A Dynamic Web Application to Bridge Genomics, Proteomics and 3D Structural Data to Guide Interpretation of Human Genetic Variants. J mol biol, Vol.431 (13), pp. 2460-2466. show abstract
PhyreRisk is an open-access, publicly accessible web application for interactively bridging genomic, proteomic and structural data facilitating the mapping of human variants onto protein structures. A major advance over other tools for sequence-structure variant mapping is that PhyreRisk provides information on 20,214 human canonical proteins and an additional 22,271 alternative protein sequences (isoforms). Specifically, PhyreRisk provides structural coverage (partial or complete) for 70% (14,035 of 20,214 canonical proteins) of the human proteome, by storing 18,874 experimental structures and 84,818 pre-built models of canonical proteins and their isoforms generated using our in house Phyre2. PhyreRisk reports 55,732 experimentally, multi-validated protein interactions from IntAct and 24,260 experimental structures of protein complexes. Another major feature of PhyreRisk is that, rather than presenting a limited set of precomputed variant-structure mapping of known genetic variants, it allows the user to explore novel variants using, as input, genomic coordinates formats (Ensembl, VCF, reference SNP ID and HGVS notations) and Human Build GRCh37 and GRCh38. PhyreRisk also supports mapping variants using amino acid coordinates and searching for genes or proteins of interest. PhyreRisk is designed to empower researchers to translate genetic data into protein structural information, thereby providing a more comprehensive appreciation of the functional impact of variants. PhyreRisk is freely available at http://phyrerisk.bc.ic.ac.uk..
Law, P.J., Timofeeva, M., Fernandez-Rozadilla, C., Broderick, P., Studd, J., Fernandez-Tajes, J., Farrington, S., Svinti, V., Palles, C., Orlando, G., et al. (2019). Association analyses identify 31 new risk loci for colorectal cancer susceptibility. Nat commun, Vol.10 (1), p. 2154. show abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention..
Atkins, I., Kinnersley, B., Ostrom, Q.T., Labreche, K., Il'yasova, D., Armstrong, G.N., Eckel-Passow, J.E., Schoemaker, M.J., Nöthen, M.M., Barnholtz-Sloan, J.S., et al. (2019). Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma. Cancer res, Vol.79 (8), pp. 2065-2071. show abstract
Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 × 10-6, we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 × 10-6). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis. SIGNIFICANCE: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop..
Labreche, K., Daniau, M., Sud, A., Law, P.J., Royer-Perron, L., Holroyd, A., Broderick, P., Went, M., Benazra, M., Ahle, G., et al. (2019). A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25 3 and 3p22 1: a LOC network study. Neuro oncol, . show abstract
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL. METHODS: We performed a meta-analysis of two new genome-wide association studies of PCNSL totaling 475 cases and 1,134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single-nucleotide polymorphisms (SNPs) using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin patterns by capture Hi-C data. RESULTS: We identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 x 10-8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10-13). In contrast the lack of an association between rs41289586 and DLBCL, suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between non-coding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis. CONCLUSION: To our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL..
Hung, R.J., Spitz, M.R., Houlston, R.S., Schwartz, A.G., Field, J.K., Ying, J., Li, Y., Han, Y., Ji, X., Chen, W., et al. (2019). Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15 33 TERT-CLPTM1Ll Region. J thorac oncol, . show abstract
INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease..
Vijayakrishnan, J., Studd, J., Broderick, P., Kinnersley, B., Holroyd, A., Law, P.J., Kumar, R., Allan, J.M., Harrison, C.J., Moorman, A.V., et al. (2019). Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia (vol 9, 1340, 2018). Nature communications, Vol.10.
Takahashi, H., Cornish, A.J., Sud, A., Law, P.J., Disney-Hogg, L., Calvocoressi, L., Lu, L., Hansen, H.M., Smirnov, I., Walsh, K.M., et al. (2019). Mendelian randomization provides support for obesity as a risk factor for meningioma. Sci rep, Vol.9 (1), p. 309. show abstract
Little is known about the causes of meningioma. Obesity and obesity-related traits have been reported in several epidemiological observational studies to be risk factors for meningioma. We performed an analysis of genetic variants associated with obesity-related traits to assess the relationship with meningioma risk using Mendelian randomization (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. We considered 11 obesity-related traits, identified genetic instruments for these factors, and assessed their association with meningioma risk using data from a genome-wide association study comprising 1,606 meningioma patients and 9,823 controls. To evaluate the causal relationship between the obesity-related traits and meningioma risk, we consider the estimated odds ratio (OR) of meningioma for each genetic instrument. We identified positive associations between body mass index (odds ratio [ORSD] = 1.27, 95% confidence interval [CI] = 1.03-1.56, P = 0.028) and body fat percentage (ORSD = 1.28, 95% CI = 1.01-1.63, P = 0.042) with meningioma risk, albeit non-significant after correction for multiple testing. Associations for basal metabolic rate, diastolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, systolic blood pressure, total cholesterol, triglycerides and waist circumference with risk of meningioma were non-significant. Our analysis provides additional support for obesity being associated with an increased risk of meningioma..
Takahashi, H., Cornish, A.J., Sud, A., Law, P.J., Kinnersley, B., Ostrom, Q.T., Labreche, K., Eckel-Passow, J.E., Armstrong, G.N., Claus, E.B., et al. (2019). Publisher Correction: Mendelian randomisation study of the relationship between vitamin D and risk of glioma. Sci rep, Vol.9 (1), p. 7924. show abstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper..
Jiang, X., Finucane, H.K., Schumacher, F.R., Schmit, S.L., Tyrer, J.P., Han, Y., Michailidou, K., Lesseur, C., Kuchenbaecker, K.B., Dennis, J., et al. (2019). Shared heritability and functional enrichment across six solid cancers. Nat commun, Vol.10 (1), p. 431. show abstract
Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis..
Zheng, G., Chattopadhyay, S., Sud, A., Sundquist, K., Sundquist, J., Försti, A., Houlston, R.S., Hemminki, A. & Hemminki, K. (2019). Types of second primary cancers influence survival in chronic lymphocytic and hairy cell leukemia patients. Blood cancer j, Vol.9 (4), p. 40.
Chattopadhyay, S., Thomsen, H., Yadav, P., da Silva Filho, M.I., Weinhold, N., Nöthen, M.M., Hoffman, P., Bertsch, U., Huhn, S., Morgan, G.J., et al. (2019). Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma. Commun biol, Vol.2, p. 89. show abstract
Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, TH17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response..
Lawler, M., Alsina, D., Adams, R.A., Anderson, A.S., Brown, G., Fearnhead, N.S., Fenwick, S.W., Halloran, S.P., Hochhauser, D., Hull, M.A., et al. (2018). Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer. Gut, Vol.67 (1), pp. 179-193. show abstract
OBJECTIVE: Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes. DESIGN: RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants. RESULTS: Fifteen critical RGs are summarised below: RG1: Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment; RG2: Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk; RG3: Pressing need for prevention trials; RG4: Lack of integration of different prevention approaches; RG5: Lack of optimal strategies for CRC screening; RG6: Lack of effective triage systems for invasive investigations; RG7: Imprecise pathological assessment of CRC; RG8: Lack of qualified personnel in genomics, data sciences and digital pathology; RG9: Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices; RG10: Need for novel technologies/interventions to improve curative outcomes; RG11: Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment; RG12: Lack of reliable biomarkers to guide stage IV treatment; RG13: Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution; RG14: Lack of coordination of CRC research/funding; RG15: Lack of effective communication between relevant stakeholders. CONCLUSION: Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years..
Tanskanen, T., van den Berg, L., Välimäki, N., Aavikko, M., Ness-Jensen, E., Hveem, K., Wettergren, Y., Bexe Lindskog, E., Tõnisson, N., Metspalu, A., et al. (2018). Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci. Int j cancer, Vol.142 (3), pp. 540-546. show abstract
Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations..
Shah, V., Sherborne, A.L., Walker, B.A., Johnson, D.C., Boyle, E.M., Ellis, S., Begum, D.B., Proszek, P.Z., Jones, J.R., Pawlyn, C., et al. (2018). Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients. Leukemia, Vol.32 (1), pp. 102-110. show abstract
Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10-7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10-14) and 1.68 (P=2.18 × 10-14), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10-27) for all patients and 3.19 (P=1.23 × 10-18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10-15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment..
Disney-Hogg, L., Sud, A., Law, P.J., Cornish, A.J., Kinnersley, B., Ostrom, Q.T., Labreche, K., Eckel-Passow, J.E., Armstrong, G.N., Claus, E.B., et al. (2018). Influence of obesity-related risk factors in the aetiology of glioma. Br j cancer, Vol.118 (7), pp. 1020-1027. show abstract
BACKGROUND: Obesity and related factors have been implicated as possible aetiological factors for the development of glioma in epidemiological observation studies. We used genetic markers in a Mendelian randomisation framework to examine whether obesity-related traits influence glioma risk. This methodology reduces bias from confounding and is not affected by reverse causation. METHODS: Genetic instruments were identified for 10 key obesity-related risk factors, and their association with glioma risk was evaluated using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. The estimated odds ratio of glioma associated with each of the genetically defined obesity-related traits was used to infer evidence for a causal relationship. RESULTS: No convincing association with glioma risk was seen for genetic instruments for body mass index, waist-to-hip ratio, lipids, type-2 diabetes, hyperglycaemia or insulin resistance. Similarly, we found no evidence to support a relationship between obesity-related traits with subtypes of glioma-glioblastoma (GBM) or non-GBM tumours. CONCLUSIONS: This study provides no evidence to implicate obesity-related factors as causes of glioma..
Kinnersley, B., Houlston, R.S. & Bondy, M.L. (2018). Genome-Wide Association Studies in Glioma. Cancer epidemiol biomarkers prev, Vol.27 (4), pp. 418-428. show abstract
Since the first reports in 2009, genome-wide association studies (GWAS) have been successful in identifying germline variants associated with glioma susceptibility. In this review, we describe a chronological history of glioma GWAS, culminating in the most recent study comprising 12,496 cases and 18,190 controls. We additionally summarize associations at the 27 glioma-risk SNPs that have been reported so far. Future efforts are likely to be principally focused on assessing association of germline-risk SNPs with particular molecular subgroups of glioma, as well as investigating the functional basis of the risk loci in tumor formation. These ongoing studies will be important to maximize the impact of research into glioma susceptibility, both in terms of insight into tumor etiology as well as opportunities for clinical translation. Cancer Epidemiol Biomarkers Prev; 27(4); 418-28. ©2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer.".
Labreche, K., Kinnersley, B., Berzero, G., Di Stefano, A.L., Rahimian, A., Detrait, I., Marie, Y., Grenier-Boley, B., Hoang-Xuan, K., Delattre, J.-., et al. (2018). Diffuse gliomas classified by 1p/19q co-deletion, TERT promoter and IDH mutation status are associated with specific genetic risk loci. Acta neuropathol, Vol.135 (5), pp. 743-755. show abstract
Recent genome-wide association studies of glioma have led to the discovery of single nucleotide polymorphisms (SNPs) at 25 loci influencing risk. Gliomas are heterogeneous, hence to investigate the relationship between risk SNPs and glioma subtype we analysed 1659 tumours profiled for IDH mutation, TERT promoter mutation and 1p/19q co-deletion. These data allowed definition of five molecular subgroups of glioma: triple-positive (IDH mutated, 1p/19q co-deletion, TERT promoter mutated); TERT-IDH (IDH mutated, TERT promoter mutated, 1p/19q-wild-type); IDH-only (IDH mutated, 1p/19q wild-type, TERT promoter wild-type); triple-negative (IDH wild-type, 1p/19q wild-type, TERT promoter wild-type) and TERT-only (TERT promoter mutated, IDH wild-type, 1p/19q wild-type). Most glioma risk loci showed subtype specificity: (1) the 8q24.21 SNP for triple-positive glioma; (2) 5p15.33, 9p21.3, 17p13.1 and 20q13.33 SNPs for TERT-only glioma; (3) 1q44, 2q33.3, 3p14.1, 11q21, 11q23.3, 14q12, and 15q24.2 SNPs for IDH mutated glioma. To link risk SNPs to target candidate genes we analysed Hi-C and gene expression data, highlighting the potential role of IDH1 at 2q33.3, MYC at 8q24.21 and STMN3 at 20q13.33. Our observations provide further insight into the nature of susceptibility to glioma..
Takahashi, H., Cornish, A.J., Sud, A., Law, P.J., Kinnersley, B., Ostrom, Q.T., Labreche, K., Eckel-Passow, J.E., Armstrong, G.N., Claus, E.B., et al. (2018). Mendelian randomisation study of the relationship between vitamin D and risk of glioma. Sci rep, Vol.8 (1), p. 2339. show abstract
To examine for a causal relationship between vitamin D and glioma risk we performed an analysis of genetic variants associated with serum 25-hydroxyvitamin D (25(OH)D) levels using Mendelian randomisation (MR), an approach unaffected by biases from confounding. Two-sample MR was undertaken using genome-wide association study data. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D levels were used as instrumental variables (IVs). We calculated MR estimates for the odds ratio (OR) for 25(OH)D levels with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighted (IVW) and maximum likelihood estimation (MLE) methods. A non-significant association between 25(OH)D levels and glioma risk was shown using both the IVW (OR = 1.21, 95% confidence interval [CI] = 0.90-1.62, P = 0.201) and MLE (OR = 1.20, 95% CI = 0.98-1.48, P = 0.083) methods. In an exploratory analysis of tumour subtype, an inverse relationship between 25(OH)D levels and glioblastoma (GBM) risk was identified using the MLE method (OR = 0.62, 95% CI = 0.43-0.89, P = 0.010), but not the IVW method (OR = 0.62, 95% CI = 0.37-1.04, P = 0.070). No statistically significant association was shown between 25(OH)D levels and non-GBM glioma. Our results do not provide evidence for a causal relationship between 25(OH)D levels and all forms of glioma risk. More evidence is required to explore the relationship between 25(OH)D levels and risk of GBM..
Shah, V., Johnson, D.C., Sherborne, A.L., Ellis, S., Aldridge, F.M., Howard-Reeves, J., Begum, F., Price, A., Kendall, J., Chiecchio, L., et al. (2018). Subclonal TP53 copy number is associated with prognosis in multiple myeloma. Blood, Vol.132 (23), pp. 2465-2469. show abstract
Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal TP53 deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; P = .01). Clonal, but not subclonal, TP53 deletions were associated with clinical markers of advanced disease, specifically lower platelet counts (P < .001) and increased lactate dehydrogenase (P < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) (P = .002) or del(1p) (P = .006). Biallelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies..
Berntsson, S.G., Merrell, R.T., Amirian, E.S., Armstrong, G.N., Lachance, D., Smits, A., Zhou, R., Jacobs, D.I., Wrensch, M.R., Olson, S.H., et al. (2018). Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case-control study. J neurol, Vol.265 (6), pp. 1432-1442. show abstract
BACKGROUND: The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls. METHODS: The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demographics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures. RESULTS: Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p < 0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood. CONCLUSIONS: Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor ***for developing glioma-related seizures or glioma..
Litchfield, K., Loveday, C., Levy, M., Dudakia, D., Rapley, E., Nsengimana, J., Bishop, D.T., Reid, A., Huddart, R., Broderick, P., et al. (2018). Large-scale Sequencing of Testicular Germ Cell Tumour (TGCT) Cases Excludes Major TGCT Predisposition Gene. Eur urol, Vol.73 (6), pp. 828-831. show abstract
Testicular germ cell tumour (TGCT), the most common cancer in young men, has a significant heritable basis that has long raised questions as to the existence of underlying major high-penetrance susceptibility gene(s). To determine the contribution of rare gene mutations to the inherited risk of TGCT, we analysed germline whole-exome data for 919 TGCT cases and 1609 cancer-free controls. We compared frequencies between TGCT cases and controls of rare (<1%) and low-frequency (1-5%) coding variants (1) individually and (2) collapsed at the gene level via burden testing (T1, disruptive; T2, all deleterious; and T3, all nonsynonymous) using Fisher's exact test with Bonferroni correction of significance thresholds. No individual variant or individual gene showed a significant association with TGCT after correction for multiple testing. In the largest whole-exome sequencing study of testicular cancer reported to date, our findings do not support the existence of a major high-penetrance TGCT susceptibility gene (of odds ratio >10 and allele frequency [combined]>0.01%). Owing to its power, this study cannot exclude the existence of susceptibility genes responsible for occasional TGCT families or of rare mutations that confer very modest relative risks. In concert with findings from genome-wide association studies, our data support the notion that inherited susceptibility is largely polygenic with substantial contribution from common variation. PATIENT SUMMARY: In the largest study of its kind, we sequenced ∼20 000 genes in 919 men with testicular germ cell tumour (TGCT) and 1609 TGCT-free individuals and found no evidence of a single major gene underlying predisposition to TGCT (in the manner of BRCA1 for breast cancer). Instead, familial risk of TGCT is likely to be due to varying dosages of hundreds of minor genetic factors..
Sud, A., Thomsen, H., Orlando, G., Försti, A., Law, P.J., Broderick, P., Cooke, R., Hariri, F., Pastinen, T., Easton, D.F., et al. (2018). Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma. Blood, Vol.132 (19), pp. 2040-2052. show abstract
To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of 7 genome-wide association studies totaling 5325 HL cases and 22 423 control patients. We identify 5 new HL risk loci at 6p21.31 (rs649775; P = 2.11 × 10-10), 6q23.3 (rs1002658; P = 2.97 × 10-8), 11q23.1 (rs7111520; P = 1.44 × 10-11), 16p11.2 (rs6565176; P = 4.00 × 10-8), and 20q13.12 (rs2425752; P = 2.01 × 10-8). Integration of gene expression, histone modification, and in situ promoter capture Hi-C data at the 5 new and 13 known risk loci implicates dysfunction of the germinal center reaction, disrupted T-cell differentiation and function, and constitutive NF-κB activation as mechanisms of predisposition. These data provide further insights into the genetic susceptibility and biology of HL..
Chattopadhyay, S., Zheng, G., Sud, A., Yu, H., Sundquist, K., Sundquist, J., Försti, A., Hemminki, A., Houlston, R. & Hemminki, K., et al. (2018). Risk of second primary cancer following myeloid neoplasia and risk of myeloid neoplasia as second primary cancer: a nationwide, observational follow up study in Sweden. Lancet haematol, Vol.5 (8), pp. e368-e377. show abstract
BACKGROUND: Although advances in the treatment of myeloid neoplasms have led to improved patient survival, this improvement has been accompanied by an increased risk of second primary cancer (ie, the risk of another cancer after myeloid neoplasia). We aimed to assess bi-directional associations between myeloid cancers and other cancers-ie, development of second primary cancer in patients who have previously had myeloid cancer, and risks of myeloid neoplasia in patients who have previously had another cancer-to provide insight into possible mechanisms beyond side-effects of treatment and shared risk factors. METHODS: Using the Swedish Family-Cancer Database, we identified 35 928 individuals with primary myeloid cancer, including myeloproliferative neoplasms, acute myeloid leukaemia, chronic myeloid leukaemia, and myelodysplastic syndrome diagnosed between 1958 and 2015. The Swedish Family-Cancer Database includes every individual registered as a resident in Sweden starting in 1932, with full parental history. The primary endpoint was the assessment of relative risks (RRs) for second primary cancer, which we performed using means of incidence rate ratios, regressed over a generalised Poisson model. FINDINGS: Between 1958 and 2015, overall relative risk of second primary cancers was significantly increased after acute myeloid leukaemia (RR 1·29, 95% CI 1·17-1·41), chronic myeloid leukaemia (1·52, 1·35-1·69), myelodysplastic syndrome (1·42, 1·26-1·59), and all myeloproliferative neoplasms (1·37, 1·30-1·43) relative to the incidence of these cancers as first primary cancer. With myeloid neoplasia as a second primary cancer, risks were significantly increased for acute myeloid leukaemia (1·57, 1·48-1·65), chronic myeloid leukaemia (1·26, 1·13-1·40), and myelodysplastic syndrome (1·54, 1·42-1·67) relative to the incidence of these myeloid neoplasms as first primary cancers. Relative risk of upper aerodigestive tract cancer, squamous cell skin cancer, and non-Hodgkin lymphoma as second primary cancers were increased after all four types of myeloid neoplasia relative to their incidence as first primary cancers. High risks of myelodysplastic syndrome and acute myeloid leukaemia as second primary cancers were found after haematological cancers (RRs between 5·08 and 10·04). INTERPRETATION: The relative risks of second primary cancer are important for the long-term management of patients with myeloid cancers. The bi-directional associations of myeloid cancers with many other cancers suggest a number of candidate mechanisms that might contribute to the development and aetiology of a second primary cancer. These mechanisms might include immune dysfunction or the effects of treatment, and these should be assessed in future investigations. FUNDING: Deutsche Krebshilfe, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Finnish Cancer Organizations, Swedish Research Council, ALF from Region Skåne, and Bloodwise..
Li, Y., Xiao, X., Han, Y., Gorlova, O., Qian, D., Leighl, N., Johansen, J.S., Barnett, M., Chen, C., Goodman, G., et al. (2018). Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population. Carcinogenesis, Vol.39 (3), pp. 336-346. show abstract
Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease..
Turnbull, C., Sud, A. & Houlston, R.S. (2018). Cancer genetics, precision prevention and a call to action. Nat genet, Vol.50 (9), pp. 1212-1218. show abstract
More than 15 years have passed since the identification, through linkage, of 'first-wave' susceptibility genes for common cancers (BRCA1, BRCA2, MLH1 and MSH2). These genes have strong frequency-penetrance profiles, such that the associated clinical utility probably remains relevant regardless of the context of ascertainment. 'Second-wave' genes, not tractable by linkage, were subsequently identified by mutation screening of candidate genes (PALB2, ATM, CHEK2, BRIP1, RAD51C and RAD51D). Their innately weaker frequency-penetrance profiles have rendered delineation of cancer associations, risks and variant pathogenicity challenging, thereby compromising their clinical application. Early germline exome-sequencing endeavors for common cancers did not yield the long-anticipated slew of 'next-wave' genes but instead implied a highly polygenic genomic architecture requiring much larger experiments to make any substantive inroads into gene discovery. As such, the 'genetic economics' of frequency penetrance clearly indicates that focused identification of carriers of first-wave-gene mutations is most impactful for cancer control. With screening, prevention and early detection at the forefront of the cancer management agenda, we propose that the time is nigh for the initiation of national population-testing programs to identify carriers of first-wave gene mutation carriers. To fully deliver a precision prevention program, long-term, large-scale mutation studies that capture longitudinal clinical data and serial biosamples are required..
Loveday, C., Law, P., Litchfield, K., Levy, M., Holroyd, A., Broderick, P., Kote-Jarai, Z., Dunning, A.M., Muir, K., Peto, J., et al. (2018). Large-scale Analysis Demonstrates Familial Testicular Cancer to have Polygenic Aetiology. Eur urol, Vol.74 (3), pp. 248-252. show abstract
Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. Early linkage analysis and recent large-scale germline exome analysis in TGCT cases demonstrate absence of major high-penetrance TGCT susceptibility gene(s). Serial genome-wide association study analyses in sporadic TGCT have in total reported 49 independent risk loci. To date, it has not been demonstrated whether familial TGCT arises due to enrichment of the same common variants underpinning susceptibility to sporadic TGCT or is due to shared environmental/lifestyle factors or disparate rare genetic TGCT susceptibility factors. Here we present polygenic risk score analysis of 37 TGCT susceptibility single-nucleotide polymorphisms in 236 familial and 3931 sporadic TGCT cases, and 12 368 controls, which demonstrates clear enrichment for TGCT susceptibility alleles in familial compared to sporadic cases (p=0.0001), with the majority of familial cases (84-100%) being attributable to polygenic enrichment. These analyses reveal TGCT as the first rare malignancy of early adulthood in which familial clustering is driven by the aggregate effects of polygenic variation in the absence of a major high-penetrance susceptibility gene. PATIENT SUMMARY: To date, it has been unclear whether familial clusters of testicular germ cell tumour (TGCT) arise due to genetics or shared environmental or lifestyle factors. We present large-scale genetic analyses comparing 236 familial TGCT cases, 3931 isolated TGCT cases, and 12 368 controls. We show that familial TGCT is caused, at least in part, by presence of a higher dose of the same common genetic variants that cause susceptibility to TGCT in general..
Ostrom, Q.T., Kinnersley, B., Wrensch, M.R., Eckel-Passow, J.E., Armstrong, G., Rice, T., Chen, Y., Wiencke, J.K., McCoy, L.S., Hansen, H.M., et al. (2018). Sex-specific glioma genome-wide association study identifies new risk locus at 3p21 31 in females, and finds sex-differences in risk at 8q24 21. Sci rep, Vol.8 (1), p. 7352. show abstract
Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex..
Claus, E.B., Cornish, A.J., Broderick, P., Schildkraut, J.M., Dobbins, S.E., Holroyd, A., Calvocoressi, L., Lu, L., Hansen, H.M., Smirnov, I., et al. (2018). Genome-wide association analysis identifies a meningioma risk locus at 11p15 5. Neuro oncol, Vol.20 (11), pp. 1485-1493. show abstract
Background: Meningiomas are adult brain tumors originating in the meningeal coverings of the brain and spinal cord, with significant heritable basis. Genome-wide association studies (GWAS) have previously identified only a single risk locus for meningioma, at 10p12.31. Methods: To identify a susceptibility locus for meningioma, we conducted a meta-analysis of 2 GWAS, imputed using a merged reference panel from the 1000 Genomes Project and UK10K data, with validation in 2 independent sample series totaling 2138 cases and 12081 controls. Results: We identified a new susceptibility locus for meningioma at 11p15.5 (rs2686876, odds ratio = 1.44, P = 9.86 × 10-9). A number of genes localize to the region of linkage disequilibrium encompassing rs2686876, including RIC8A, which plays a central role in the development of neural crest-derived structures, such as the meninges. Conclusions: This finding advances our understanding of the genetic basis of meningioma development and provides additional support for a polygenic model of meningioma..
Vijayakrishnan, J., Studd, J., Broderick, P., Kinnersley, B., Holroyd, A., Law, P.J., Kumar, R., Allan, J.M., Harrison, C.J., Moorman, A.V., et al. (2018). Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia. Nat commun, Vol.9 (1), p. 1340. show abstract
Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology..
Orlando, G., Law, P.J., Cornish, A.J., Dobbins, S.E., Chubb, D., Broderick, P., Litchfield, K., Hariri, F., Pastinen, T., Osborne, C.S., et al. (2018). Promoter capture Hi-C-based identification of recurrent noncoding mutations in colorectal cancer. Nat genet, Vol.50 (10), pp. 1375-1380. show abstract
Efforts are being directed to systematically analyze the non-coding regions of the genome for cancer-driving mutations1-6. cis-regulatory elements (CREs) represent a highly enriched subset of the non-coding regions of the genome in which to search for such mutations. Here we use high-throughput chromosome conformation capture techniques (Hi-C) for 19,023 promoter fragments to catalog the regulatory landscape of colorectal cancer in cell lines, mapping CREs and integrating these with whole-genome sequence and expression data from The Cancer Genome Atlas7,8. We identify a recurrently mutated CRE interacting with the ETV1 promoter affecting gene expression. ETV1 expression influences cell viability and is associated with patient survival. We further refine our understanding of the regulatory effects of copy-number variations, showing that RASL11A is targeted by a previously identified enhancer amplification1. This study reveals new insights into the complex genetic alterations driving tumor development, providing a paradigm for employing chromosome conformation capture to decipher non-coding CREs relevant to cancer biology..
Hoang, P.H., Dobbins, S.E., Cornish, A.J., Chubb, D., Law, P.J., Kaiser, M. & Houlston, R.S. (2018). Whole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms. Leukemia, Vol.32 (11), pp. 2459-2470.
Hoang, P.H., Dobbins, S.E., Cornish, A.J., Chubb, D., Law, P.J., Kaiser, M. & Houlston, R.S. (2018). Whole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms. Leukemia, Vol.32 (11), pp. 2459-2470. show abstract
Multiple myeloma (MM) is a biologically heterogeneous malignancy, however, the mechanisms underlying this complexity are incompletely understood. We report an analysis of the whole-genome sequencing of 765 MM patients from CoMMpass. By employing promoter capture Hi-C in naïve B-cells, we identify cis-regulatory elements (CREs) that represent a highly enriched subset of the non-coding genome in which to search for driver mutations. We identify regulatory regions whose mutation significantly alters the expression of genes as candidate non-coding drivers, including copy number variation (CNV) at CREs of MYC and single-nucleotide variants (SNVs) in a PAX5 enhancer. To better inform the interplay between non-coding driver mutations with other driver mechanisms, and their respective roles in oncogenic pathways, we extended our analysis identifying coding drivers in 40 genes, including 11 novel candidates. We demonstrate the same pathways can be targeted by coding and non-coding mutations; exemplified by IRF4 and PRDM1, along with BCL6 and PAX5, genes that are central to plasma cell differentiation. This study reveals new insights into the complex genetic alterations driving MM development and an enhanced understanding of oncogenic pathways..
Kinnersley, B., Sud, A., Coker, E.A., Tym, J.E., Di Micco, P., Al-Lazikani, B. & Houlston, R.S. (2018). Leveraging Human Genetics to Guide Cancer Drug Development. Jco clin cancer inform, Vol.2, pp. 1-11. show abstract
PURPOSE: The high attrition rate of cancer drug development programs is a barrier to realizing the promise of precision oncology. We have examined whether the genetic insights from genome-wide association studies of cancer can guide drug development and repurposing in oncology. MATERIALS AND METHODS: Across 37 cancers, we identified 955 genetic risk variants from the National Human Genome Research Institute-European Bioinformatics Institute genome-wide association study catalog. We linked these variants to target genes using strategies that were based on linkage disequilibrium, DNA three-dimensional structure, and integration of predicted gene function and expression. With the use of the Informa Pharmaprojects database, we identified genes that are targets of unique drugs and assessed the level of enrichment that would be afforded by incorporation of genetic information in preclinical and phase II studies. For targets not under development, we implemented machine learning approaches to assess druggability. RESULTS: For all preclinical targets incorporating genetic information, a 2.00-fold enrichment of a drug being successfully approved could be achieved (95% CI, 1.14- to 3.48-fold; P = .02). For phase II targets, a 2.75-fold enrichment could be achieved (95% CI, 1.42- to 5.35-fold; P < .001). Application of genetic information suggests potential repurposing of 15 approved nononcology drugs. CONCLUSION: The findings illustrate the value of using insights from the genetics of inherited cancer susceptibility discovery projects as part of a data-driven strategy to inform drug discovery. Support for cancer germline genetic information for prospective targets is available online from the Institute of Cancer Research..
Ji, X., Bossé, Y., Landi, M.T., Gui, J., Xiao, X., Qian, D., Joubert, P., Lamontagne, M., Li, Y., Gorlov, I., et al. (2018). Identification of susceptibility pathways for the role of chromosome 15q25 1 in modifying lung cancer risk. Nat commun, Vol.9 (1), p. 3221. show abstract
Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer..
Went, M., Sud, A., Försti, A., Halvarsson, B.-., Weinhold, N., Kimber, S., van Duin, M., Thorleifsson, G., Holroyd, A., Johnson, D.C., et al. (2018). Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nat commun, Vol.9 (1), p. 3707. show abstract
Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM..
He, Y., Timofeeva, M., Farrington, S.M., Vaughan-Shaw, P., Svinti, V., Walker, M., Zgaga, L., Meng, X., Li, X., Spiliopoulou, A., et al. (2018). Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study. Bmc med, Vol.16 (1), p. 142. show abstract
BACKGROUND: Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. METHODS: We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. RESULTS: The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 × 10- 11), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51-2.07, P = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69-1.19, P = 0.48). CONCLUSIONS: Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven..
Ostrom, Q.T., Kinnersley, B., Armstrong, G., Rice, T., Chen, Y., Wiencke, J.K., McCoy, L.S., Hansen, H.M., Amos, C.I., Bernstein, J.L., et al. (2018). Age-specific genome-wide association study in glioblastoma identifies increased proportion of 'lower grade glioma'-like features associated with younger age. Int j cancer, Vol.143 (10), pp. 2359-2366. show abstract
Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18-53, 54-64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54-63 = 1.50x10-9 , OR54-63 = 1.28, 95%CI54-63 = 1.18-1.39; p64+ = 2.14x10-11 , OR64+ = 1.32, 95%CI64+ = 1.21-1.43] and rs11979158 [p54-63 = 6.13x10-8 , OR54-63 = 1.35, 95%CI54-63 = 1.21-1.50; p64+ = 2.18x10-10 , OR64+ = 1.42, 95%CI64+ = 1.27-1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18-53 (p18-53 = 9.30 × 10-11 , OR18-53 = 1.76, 95%CI18-53 = 1.49-2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of 'LGG'-like tumor characteristics in GBM samples in those 18-53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54-63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18-53 suggests that more younger individuals may present initially with 'secondary glioblastoma.'.
Chattopadhyay, S., Sud, A., Zheng, G., Yu, H., Sundquist, K., Sundquist, J., Försti, A., Houlston, R., Hemminki, A. & Hemminki, K., et al. (2018). Second primary cancers in non-Hodgkin lymphoma: Bidirectional analyses suggesting role for immune dysfunction. Int j cancer, Vol.143 (10), pp. 2449-2457. show abstract
Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses. It is unlikely that prior therapy is solely responsible for SPC risk. To investigate risk of SPC after diagnosis of non-Hodgkin lymphoma (NHL) and 10 of its subtypes we conducted a novel bidirectional analysis, SPCs after NHL and NHL as SPC. Using the Swedish Family-Cancer Database, we identified 19,833 individuals with primary NHL diagnosed between 1993 and 2015. We calculated relative risks (RRs) of SPCs in NHL survivors and, for bi-directional analysis, risk of NHL as SPC. The overall RRs were significantly bidirectionally increased for NHL and 7 cancers. After diagnosis of NHL risks were increased for upper aerodigestive tract (RR = 1.96), colorectal (1.35), kidney (3.10), bladder (1.54) and squamous cell skin cancer (SCC) (4.12), melanoma (1.98) and Hodgkin lymphoma (9.38). The concordance between RRs for each bidirectional association between NHL and 31 different cancers was highly significant (r = 0.86, p < 0.0001). Melanoma was bidirectionally associated with all 10 subtypes of NHL. The observed bidirectional associations between NHL and cancer suggest that therapy-related carcinogenic mechanisms cannot solely explain the findings. Considering that skin SCC and melanoma are usually treated by surgery and that these cancers and NHL are most responsive of any cancer to immune suppression, the consistent bidirectional results provide population-level evidence that immune suppressed state is a key underlying mechanism in the context of SPCs. Furthermore, the quantified risks for NHL subtypes have direct clinical application in the management of NHL patients..
Disney-Hogg, L., Cornish, A.J., Sud, A., Law, P.J., Kinnersley, B., Jacobs, D.I., Ostrom, Q.T., Labreche, K., Eckel-Passow, J.E., Armstrong, G.N., et al. (2018). Impact of atopy on risk of glioma: a Mendelian randomisation study. Bmc med, Vol.16 (1), p. 42. show abstract
BACKGROUND: An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. METHODS: Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis. RESULTS: Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93-1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94-0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91-1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92-1.02, P = 0.194). CONCLUSIONS: Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions..
Went, M., Sud, A., Speedy, H., Sunter, N.J., Försti, A., Law, P.J., Johnson, D.C., Mirabella, F., Holroyd, A., Li, N., et al. (2018). Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology. Blood cancer j, Vol.9 (1), p. 1. show abstract
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies..
Studd, J.B., Vijayakrishnan, J., Yang, M., Migliorini, G., Paulsson, K. & Houlston, R.S. (2018). Author Correction: Genetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10q21 2. Nat commun, Vol.9, p. 16204. show abstract
This corrects the article DOI: 10.1038/ncomms14616..
Loveday, C., Litchfield, K., Levy, M., Holroyd, A., Broderick, P., Kote-Jarai, Z., Dunning, A.M., Muir, K., Peto, J., Eeles, R., et al. (2018). Validation of loci at 2q14 2 and 15q21 3 as risk factors for testicular cancer. Oncotarget, Vol.9 (16), pp. 12630-12638. show abstract
Testicular germ cell tumor (TGCT), the most common cancer in men aged 18 to 45 years, has a strong heritable basis. Genome-wide association studies (GWAS) have proposed single nucleotide polymorphisms (SNPs) at a number of loci influencing TGCT risk. To further evaluate the association of recently proposed risk SNPs with TGCT at 2q14.2, 3q26.2, 7q36.3, 10q26.13 and 15q21.3, we analyzed genotype data on 3,206 cases and 7,422 controls. Our analysis provides independent replication of the associations for risk SNPs at 2q14.2 (rs2713206 at P = 3.03 × 10-2; P-meta = 3.92 × 10-8; nearest gene, TFCP2L1) and rs12912292 at 15q21.3 (P = 7.96 × 10-11; P-meta = 1.55 × 10-19; nearest gene PRTG). Case-only analyses did not reveal specific associations with TGCT histology. TFCP2L1 joins the growing list of genes located within TGCT risk loci with biologically plausible roles in developmental transcriptional regulation, further highlighting the importance of this phenomenon in TGCT oncogenesis..
Sud, A., Chattopadhyay, S., Thomsen, H., Sundquist, K., Sundquist, J., Houlston, R.S. & Hemminki, K. (2018). Familial risks of acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms. Blood, Vol.132 (9), pp. 973-976.
Sud, A., Thomsen, H., Law, P.J., Försti, A., Filho, M.I., Holroyd, A., Broderick, P., Orlando, G., Lenive, O., Wright, L., et al. (2017). Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility. Nat commun, Vol.8 (1), p. 1892. show abstract
Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10-8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10-17), 6q23.3 (rs6928977, P = 4.62 × 10-11), 10p14 (rs3781093, P = 9.49 × 10-13), 13q34 (rs112998813, P = 4.58 × 10-8) and 16p13.13 (rs34972832, P = 2.12 × 10-8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response..
Gu, F., Zhang, H., Hyland, P.L., Berndt, S., Gapstur, S.M., Wheeler, W., Ellipse Consortium, T., Amos, C.I., Bezieau, S., Bickeböller, H., et al. (2017). Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia. Int j cancer, Vol.141 (9), pp. 1794-1802. show abstract
Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway < 0.00625). The two most significant genes were NPAS2 (pgene = 0.0062) and AANAT (pgene = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway = 0.021); this association was not confirmed in GECCO (ppathway = 0.76) or the combined data (ppathway = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms..
Liu, H., Liu, Z., Wang, Y., Stinchcombe, T.E., Owzar, K., Han, Y., Hung, R.J., Brhane, Y., McLaughlin, J., Brennan, P., et al. (2017). Functional variants in DCAF4 associated with lung cancer risk in European populations. Carcinogenesis, Vol.38 (5), pp. 541-551. show abstract
Cullin-RING ubiquitin ligases (CRLs) responsible for substrate specificity of ubiquitination play a key role in cell-cycle control and DNA damage response. In this study, we assessed associations between 16 599 SNPs in 115 CRL genes and lung cancer risk by using summary data of six published genome-wide association studies (GWASs) of 12 160 cases and 16 838 cases of European ancestry. As a result, we identified three independent SNPs in DCAF4 (rs117781739, rs12587742 and rs2240980) associated with lung cancer risk (odds ratio = 0.91, 1.09 and 1.09, respectively; 95% confidence interval = 0.88-0.95, 1.05-1.14 and 1.05-1.13, respectively; and P = 3.99 × 10-6, 4.97 × 10-5 and 1.44 × 10-5, respectively) after multiple comparison correction by a false discovery rate <0.05. Since SNP rs12587742 is located within the promoter region and one CpG island of DCAF4, we further performed in silico functional analyses and found that the rs12587742 variant A allele was associated with an increased mRNA expression (P = 2.20 × 10-16, 1.79 × 10-13 and 0.001 in blood cells, normal lung tissues and tumor tissues of lung squamous carcinoma, respectively) and a decreased methylation status (P = 2.48 × 10-9 and 0.032 in adipose and lung tumor tissues, respectively). Moreover, evidence from differential expression analyses further supported an oncogenic effect of DCAF4 on lung cancer, with higher mRNA levels in both lung squamous carcinoma and adenocarcinoma (P = 4.48 × 10-11 and 1.22 × 10-9, respectively) than in adjacent normal tissues. Taken together, our results suggest that rs12587742 is associated with an increased lung cancer risk, possibly by up-regulating mRNA expression and decreasing methylation status of DCAF4..
Macauda, A., Calvetti, D., Maccari, G., Hemminki, K., Försti, A., Goldschmidt, H., Weinhold, N., Houlston, R., Andersen, V., Vogel, U., et al. (2017). Identification of miRSNPs associated with the risk of multiple myeloma. Int j cancer, Vol.140 (3), pp. 526-534. show abstract
Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta-analyzed with data from a previously published genome-wide association study (GWAS). The SNPs rs13409 (located in the 3'UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome-wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk..
Broderick, P., Dobbins, S.E., Chubb, D., Kinnersley, B., Dunlop, M.G., Tomlinson, I. & Houlston, R.S. (2017). Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review. Gastroenterology, Vol.152 (1), pp. 75-77.e4. show abstract
High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene. We found sufficient evidence for NTHL1 to be considered a CRC predisposition gene-members of 3 unrelated Dutch families were homozygous for inactivating p.Gln90Ter mutations; a Canadian woman with polyposis, CRC, and multiple tumors was reported to be heterozygous for the inactivating NTHL1 p.Gln90Ter/c.709+1G>A mutations; and a man with polyposis was reported to carry p.Gln90Ter/p.Gln287Ter; whereas no inactivating homozygous or compound heterozygous mutations were detected in controls. Variants that disrupted RPS20 were detected in a Finnish family with early-onset CRC (p.Val50SerfsTer23), a 39-year old individual with metachronous CRC (p.Leu61GlufsTer11 mutation), and a 41-year-old individual with CRC (missense p.Val54Leu), but not in controls. We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC, but not of other recently reported CRC susceptibility variants. We urge the research community to adopt rigorous statistical and biological approaches coupled with independent replication before making claims of pathogenicity..
Sud, A., Hemminki, K. & Houlston, R.S. (2017). Second cancer risk following Hodgkin lymphoma. Oncotarget, Vol.8 (45), pp. 78261-78262.
Studd, J.B., Vijayakrishnan, J., Yang, M., Migliorini, G., Paulsson, K. & Houlston, R.S. (2017). Genetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10p21 2. Nat commun, Vol.8, p. 14616. show abstract
Despite high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL) being the most common subgroup of paediatric ALL, its aetiology remains unknown. Genome-wide association studies have demonstrated association at 10q21.2. Here, we sought to determine how this region influences HD-ALL risk. We impute genotypes across the locus, finding the single nucleotide polymorphism rs7090445 highly associated with HD-ALL (P=1.54 × 10-38), and residing in a predicted enhancer element. We show this region physically interacts with the transcription start site of ARID5B, that alleles of rs7090445 have differential enhancer activity and influence RUNX3 binding. RUNX3 knock-down reduces ARID5B expression and rs7090445 enhancer activity. Individuals carrying the rs7090445-C risk allele also have reduced ARID5B expression. Finally, the rs7090445-C risk allele is preferentially retained in HD-ALL blasts consistent with inherited genetic variation contributing to arrest of normal lymphocyte development, facilitating leukaemic clonal expansion. These data provide evidence for a biological mechanism underlying hereditary risk of HD-ALL at 10q21.2..
Vijayakrishnan, J., Kumar, R., Henrion, M.Y., Moorman, A.V., Rachakonda, P.S., Hosen, I., da Silva Filho, M.I., Holroyd, A., Dobbins, S.E., Koehler, R., et al. (2017). A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26 13 and 12q23 1. Leukemia, Vol.31 (3), pp. 573-579. show abstract
Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10-11) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10-9). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology..
Frampton, M. & Houlston, R.S. (2017). Modeling the prevention of colorectal cancer from the combined impact of host and behavioral risk factors. Genet med, Vol.19 (3), pp. 314-321. show abstract
PURPOSE: This study investigated the utility of modeling modifiable lifestyle risk factors in addition to genetic variation in colorectal cancer (CRC) screening/prevention. METHODS: We derived a polygenic risk score for CRC susceptibility variants in combination with the established nongenetic risk factors of inflammatory bowel disease (IBD), adiposity, alcohol, red meat, fruit, vegetables, smoking, physical activity, and aspirin. We used the 37 known risk variants and 50 and 100% of all risk variants as calculated from a heritability estimate. We derived absolute risk from UK population age structure, incidence, and mortality rate data. RESULTS: Taking into account all risk factors (known variants), 42.2% of 55- to 59-year-old men with CRC have a risk at least as high as that of an average 60-year-old, the minimum eligible age for the UK NHS National Bowel Cancer Screening Program. If the male population is stratified by known variants and IBD status, then risk-difference estimates imply that for 10,000 50-year-old men in the 99th percentile, 760 cases could be prevented over a 25-year period through the modifiable risk factors, but in the lowest percentile, only 90 could be prevented. CONCLUSION: CRC screening and prevention centered on modifiable risk factors could be optimized if targeted at individuals at higher polygenic risk.Genet Med 19 3, 314-321..
Sud, A., Hemminki, K. & Houlston, R.S. (2017). Candidate gene association studies and risk of Hodgkin lymphoma: a systematic review and meta-analysis. Hematol oncol, Vol.35 (1), pp. 34-50. show abstract
To evaluate the contribution of association studies of candidate polymorphisms to inherited predisposition to Hodgkin lymphoma (HL), we conducted a systematic review and meta-analysis of published case-control studies. Of the variants examined more than once in candidate gene association studies, we identified 21 studies that reported on 12 polymorphic variants in 10 genes. Data were also extracted from a published genome wide association study to allow analysis of an additional 47 variants in a further 30 genes. Promising associations were seen in nine of the variants (p < 0.05). Given that the estimated false positive report probabilities (FPRPs) for all associations are high (i.e. FPRP > 0.2), these findings should be interpreted with caution. While studies of candidate polymorphisms may be an attractive means of identifying risk factors for HL, future studies should employ sample sizes adequately powered to identify variants having only modest effects on HL risk. Furthermore, because of aetiological heterogeneity within HL, stratification of genotyping according to age, tumour Epstein-Barr virus status and histology is essential. Copyright © 2015 John Wiley & Sons, Ltd..
Zhou, F., Wang, Y., Liu, H., Ready, N., Han, Y., Hung, R.J., Brhane, Y., McLaughlin, J., Brennan, P., Bickeböller, H., et al. (2017). Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs. Mol carcinog, Vol.56 (4), pp. 1227-1238. show abstract
PURPOSE: mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk. EXPERIMENTAL DESIGN: Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci. RESULTS: This pathway-based analysis included 6816 single nucleotide polymorphisms (SNP) in 68 genes in 14 463 lung cancer cases and 44 188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score "1f" was chosen as the tagSNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04-1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association. CONCLUSION: The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk. © 2016 Wiley Periodicals, Inc..
Johnson, D.C., Lenive, O., Mitchell, J., Jackson, G., Owen, R., Drayson, M., Cook, G., Jones, J.R., Pawlyn, C., Davies, F.E., et al. (2017). Neutral tumor evolution in myeloma is associated with poor prognosis. Blood, Vol.130 (14), pp. 1639-1643. show abstract
Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcomes, we analyzed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase 3 trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory drug (IMiD) therapy. By analyzing mutant allele frequency distributions in tumors, we found that 17% to 20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in nonintensively treated patients, which is consistent with the reduced therapeutic efficacy of microenvironment-modulating IMiDs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcomes and personalizing therapy..
Melin, B.S., Barnholtz-Sloan, J.S., Wrensch, M.R., Johansen, C., Il'yasova, D., Kinnersley, B., Ostrom, Q.T., Labreche, K., Chen, Y., Armstrong, G., et al. (2017). Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors. Nat genet, Vol.49 (5), pp. 789-794. show abstract
Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology..
Tamm, R., Mägi, R., Tremmel, R., Winter, S., Mihailov, E., Smid, A., Möricke, A., Klein, K., Schrappe, M., Stanulla, M., et al. (2017). Polymorphic variation in TPMT is the principal determinant of TPMT phenotype: A meta-analysis of three genome-wide association studies. Clin pharmacol ther, Vol.101 (5), pp. 684-695. show abstract
Thiopurine-related hematotoxicity in pediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 pediatric ALL cases. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including the TPMT gene region, were significantly associated with TPMT activity (P < 5.0 × 10-8 ) in each of the three GWAS and a joint meta-analysis of 1,212 cases (top hit P = 1.2 × 10-72 ). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize mercaptopurine dosage..
Yin, J., Liu, H., Liu, Z., Owzar, K., Han, Y., Su, L., Wei, Y., Hung, R.J., Brhane, Y., McLaughlin, J., et al. (2017). Pathway-analysis of published genome-wide association studies of lung cancer: A potential role for the CYP4F3 locus. Mol carcinog, Vol.56 (6), pp. 1663-1672. show abstract
The fatty acids (FAs) metabolism is suggested to play a pivotal role in the development of lung cancer, and we explored that by conducting a pathway-based analysis. We performed a meta-analysis of published datasets of six genome wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, which included 12 160 cases with lung cancer and 16 838 cancer-free controls. A total of 30 722 single-nucleotide polymorphisms (SNPs) from 317 genes relevant to FA metabolic pathways were identified. An additional dataset from the Harvard Lung Cancer Study with 984 cases and 970 healthy controls was also added to the final meta-analysis. In the initial meta-analysis, 26 of 28 SNPs that passed false discovery rate multiple tests were mapped to the CYP4F3 gene. Among the 26 top ranked hits was a proxy SNP, CYP4F3 rs4646904 (P = 8.65 × 10-6 , FDR = 0.018), which is suggested to change splicing pattern/efficiency and to be associated with gene expression levels. However, after adding data of rs4646904 from the Harvard GWAS, the significance in the combined analysis was reduced to P = 3.52 × 10-3 [odds ratio (OR) = 1.07, 95% confidence interval (95%CI) = 1.03-1.12]. Interestingly, the small Harvard dataset also pointed to the same direction of the association in subgroups of smokers (OR = 1.07) and contributed to a combined OR of 1.13 (95% CI = 1.06-1.20, P = 6.70 × 10-5 ). The results suggest that a potentially functional SNP in CYP4F3 (rs4646904) may contribute to the etiology of lung cancer, especially in smokers. Additional mechanistic studies are warranted to unravel the potential biological significance of the finding..
Rasche, L., Angtuaco, E., McDonald, J.E., Buros, A., Stein, C., Pawlyn, C., Thanendrarajan, S., Schinke, C., Samant, R., Yaccoby, S., et al. (2017). Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood, Vol.130 (1), pp. 30-34. show abstract
18F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging with background signal suppression (DWIBS) are 2 powerful functional imaging modalities in the evaluation of malignant plasma cell (PC) disease multiple myeloma (MM). Preliminary observations have suggested that MM patients with extensive disease according to DWIBS may be reported as being disease-free on FDG-PET ("PET false-negative"). The aim of this study was to describe the proportion of PET false-negativity in a representative set of 227 newly diagnosed MM patients with simultaneous assessment of FDG-PET and DWIBS, and to identify tumor-intrinsic features associated with this pattern. We found the incidence of PET false-negativity to be 11%. Neither tumor load-associated parameters, such as degree of bone marrow PC infiltration, nor the PC proliferation rate were associated with this subset. However, the gene coding for hexokinase-2, which catalyzes the first step of glycolysis, was significantly lower expressed in PET false-negative cases (5.3-fold change, P < .001) which provides a mechanistic explanation for this feature. In conclusion, we demonstrate a relevant number of patients with FDG-PET false-negative MM and a strong association between hexokinase-2 expression and this negativity: a finding which may also be relevant for clinical imaging of other hematological cancers..
Shah, V., Boyd, K.D., Houlston, R.S. & Kaiser, M.F. (2017). Constitutional mutation in CDKN2A is associated with long term survivorship in multiple myeloma: a case report. Bmc cancer, Vol.17 (1), p. 718. show abstract
BACKGROUND: Multiple Myeloma is a cancer of plasma cells associated with significantly reduced survival. Long term survivorship from myeloma is very rare and despite advances in its treatment the disease is generally considered incurable. We report a patient diagnosed with myeloma carrying a germline mutation of a tumour suppressor gene who has effectively been cured. CASE PRESENTATION: A 36-year-old woman was diagnosed with IgG lambda myeloma in 1985. She was treated with melphalan chemotherapy followed by high-dose melphalan and autologous stem cell rescue and since remained in complete remission despite not having received any additional therapy. After eliciting a prior history of multiple primary melanomas and breast cancer, she was tested for and shown to be a carrier for a germline mutation in CDKN2A. CONCLUSIONS: This is the second case report of germline mutation of CDKN2A being associated with myeloma. CDKN2A is a stabiliser of p53. Long term survivorship after high dose DNA damaging chemotherapy with melphalan in this patient is compatible with an increased chemo-sensitivity due to impairment of the DNA repair pathway..
Law, P.J., Berndt, S.I., Speedy, H.E., Camp, N.J., Sava, G.P., Skibola, C.F., Holroyd, A., Joseph, V., Sunter, N.J., Nieters, A., et al. (2017). Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia. Nat commun, Vol.8, p. 14175. show abstract
Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10-13), 1q42.13 (rs41271473, P=1.06 × 10-10), 4q24 (rs71597109, P=1.37 × 10-10), 4q35.1 (rs57214277, P=3.69 × 10-8), 6p21.31 (rs3800461, P=1.97 × 10-8), 11q23.2 (rs61904987, P=2.64 × 10-11), 18q21.1 (rs1036935, P=3.27 × 10-8), 19p13.3 (rs7254272, P=4.67 × 10-8) and 22q13.33 (rs140522, P=2.70 × 10-9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response..
Litchfield, K., Levy, M., Orlando, G., Loveday, C., Law, P.J., Migliorini, G., Holroyd, A., Broderick, P., Karlsson, R., Haugen, T.B., et al. (2017). Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor. Nat genet, Vol.49 (7), pp. 1133-1140. show abstract
Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT..
da Silva Filho, M.I., Försti, A., Weinhold, N., Meziane, I., Campo, C., Huhn, S., Nickel, J., Hoffmann, P., Nöthen, M.M., Jöckel, K.-., et al. (2017). Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts: comparison with myeloma. Leukemia, Vol.31 (8), pp. 1735-1742. show abstract
Immunoglobulin light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibers derived from immunoglobulin light chain. AL amyloidosis and multiple myeloma (MM) originate from monoclonal gammopathy of undetermined significance. We wanted to characterize germline susceptibility to AL amyloidosis using a genome-wide association study (GWAS) on 1229 AL amyloidosis patients from Germany, UK and Italy, and 7526 healthy local controls. For comparison with MM, recent GWAS data on 3790 cases were used. For AL amyloidosis, single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at P<10-5 with homogeneity of results from the 3 sample sets; some of these were previously documented to influence MM risk, including the SNP at the IRF4 binding site. In AL amyloidosis, rs9344 at the splice site of cyclin D1, promoting translocation (11;14), reached the highest significance, P=7.80 × 10-11; the SNP was only marginally significant in MM. SNP rs79419269 close to gene SMARCD3 involved in chromatin remodeling was also significant (P=5.2 × 10-8). These data provide evidence for common genetic susceptibility to AL amyloidosis and MM. Cyclin D1 is a more prominent driver in AL amyloidosis than in MM, but the links to aggregation of light chains need to be demonstrated..
Levy, M., Hall, D., Sud, A., Law, P., Litchfield, K., Dudakia, D., Haugen, T.B., Karlsson, R., Reid, A., Huddart, R.A., et al. (2017). Mendelian randomisation analysis provides no evidence for a relationship between adult height and testicular cancer risk. Andrology, Vol.5 (5), pp. 914-922. show abstract
Observational studies have suggested anthropometric traits, particularly increased height are associated with an elevated risk of testicular cancer (testicular germ cell tumour). However, there is an inconsistency between study findings, suggesting the possibility of the influence of confounding factors. To examine the association between anthropometric traits and testicular germ cell tumour using an unbiased approach, we performed a Mendelian randomisation study. We used genotype data from genome wide association studies of testicular germ cell tumour totalling 5518 cases and 19,055 controls. Externally weighted polygenic risk scores were created and used to evaluate associations with testicular germ cell tumour risk per one standard deviation (s.d) increase in genetically-defined adult height, adult BMI, adult waist hip ratio adjusted for BMI (WHRadjBMI), adult hip circumference adjusted for BMI (HIPadjBMI), adult waist circumference adjusted for BMI (WCadjBMI), birth weight (BW) and childhood obesity. Mendelian randomisation analysis did not demonstrate an association between any anthropometric trait and testicular germ cell tumour risk. In particular, despite good power, there was no global evidence for association between height and testicular germ cell tumour. However, three SNPs for adult height individually showed association with testicular germ cell tumour (rs4624820: OR = 1.47, 95% CI: 1.41-1.55, p = 2.7 × 10-57 ; rs12228415: OR = 1.17, 95% CI: 1.11-1.22, p = 3.1 × 10-10 ; rs7568069: OR = 1.13, 95% CI: 1.07-1.18, p = 1.1 × 10-6 ). This Mendelian randomisation analysis, based on the largest testicular germ cell tumour genome wide association dataset to date, does not support a causal etiological association between anthropometric traits and testicular germ cell tumour aetiology. Our findings are more compatible with confounding by shared environmental factors, possibly related to prenatal growth with exposure to these risk factors occurring in utero..
Scelo, G., Purdue, M.P., Brown, K.M., Johansson, M., Wang, Z., Eckel-Passow, J.E., Ye, Y., Hofmann, J.N., Choi, J., Foll, M., et al. (2017). Genome-wide association study identifies multiple risk loci for renal cell carcinoma. Nat commun, Vol.8, p. 15724. show abstract
Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility..
May-Wilson, S., Sud, A., Law, P.J., Palin, K., Tuupanen, S., Gylfe, A., Hänninen, U.A., Cajuso, T., Tanskanen, T., Kondelin, J., et al. (2017). Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis. Eur j cancer, Vol.84, pp. 228-238. show abstract
BACKGROUND: While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk. METHODS: We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels. RESULTS: Risk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65-0.92, P = 3.9 × 10-3; ORPOA = 0.36, 95% CI: 0.15-0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93-0.98, P = 3.7 × 10-4; ORAA = 1.05, 95% CI: 1.02-1.07, P = 1.7 × 10-4). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01-1.35, P = 0.041). CONCLUSION: Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk..
Meziane, I., Huhn, S., Filho, M.I., Weinhold, N., Campo, C., Nickel, J., Hoffmann, P., Nöthen, M.M., Jöckel, K.-., Landi, S., et al. (2017). Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts. Haematologica, Vol.102 (10), pp. e411-e414.
Sud, A., Thomsen, H., Sundquist, K., Houlston, R.S. & Hemminki, K. (2017). Risk of Second Cancer in Hodgkin Lymphoma Survivors and Influence of Family History. J clin oncol, Vol.35 (14), pp. 1584-1590. show abstract
Purpose Although advances in Hodgkin lymphoma (HL) treatment have led to improved disease-free survival, this has been accompanied by an increased risk of second cancers. We sought to quantify the second cancer risks and to investigate the impact of family history. Patients and Methods Using the Swedish Family-Cancer Project Database, we identified 9,522 individuals with primary HL diagnosed between 1965 and 2012. We calculated standardized incidence ratios and cumulative incidence of second cancer in HL survivors and compared the standardized incidence ratios of lung, breast, colorectal, and all second cancers in HL survivors with and without a site-specific family history of cancer. Interactions between family history of cancer and HL treatment were evaluated under additive and multiplicative models. Results Overall, the risk of a second cancer in HL survivors was increased 2.39-fold (95% CI, 2.29 to 2.53). The 30-year cumulative incidence of breast cancer in women diagnosed with HL at younger than 35 years of age was 13.8%. We observed no significant difference in cancer risk over successive time periods. The risk of all second cancers was 1.3-fold higher for HL survivors with a first-degree relative with cancer ( P < .001), with 3.3-fold, 2.1-fold, and 1.8-fold differences shown for lung, colorectal, and breast cancers, respectively. Moreover, a greater than additive interaction between family history of lung cancer and HL treatment was shown ( P = .03). Conclusion HL survivorship is associated with a substantive risk of a second cancer. Notably, the risk is higher in individuals with a family history of cancer. This information should be used to inform risk-adapted therapy and to assist in screening to reduce long-term morbidity and mortality in patients with HL..
Sud, A., Kinnersley, B. & Houlston, R.S. (2017). Genome-wide association studies of cancer: current insights and future perspectives. Nat rev cancer, Vol.17 (11), pp. 692-704. show abstract
Genome-wide association studies (GWAS) provide an agnostic approach for investigating the genetic basis of complex diseases. In oncology, GWAS of nearly all common malignancies have been performed, and over 450 genetic variants associated with increased risks have been identified. As well as revealing novel pathways important in carcinogenesis, these studies have shown that common genetic variation contributes substantially to the heritable risk of many common cancers. The clinical application of GWAS is starting to provide opportunities for drug discovery and repositioning as well as for cancer prevention. However, deciphering the functional and biological basis of associations is challenging and is in part a barrier to fully unlocking the potential of GWAS..
Machiela, M.J., Hofmann, J.N., Carreras-Torres, R., Brown, K.M., Johansson, M., Wang, Z., Foll, M., Li, P., Rothman, N., Savage, S.A., et al. (2017). Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma. Eur urol, Vol.72 (5), pp. 747-754. show abstract
BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma..
Feng, Y., Wang, Y., Liu, H., Liu, Z., Mills, C., Han, Y., Hung, R.J., Brhane, Y., McLaughlin, J., Brennan, P., et al. (2017). Genetic variants of PTPN2 are associated with lung cancer risk: a re-analysis of eight GWASs in the TRICL-ILCCO consortium. Sci rep, Vol.7 (1), p. 825. show abstract
The T-cell protein tyrosine phosphatase (TCPTP) pathway consists of signaling events mediated by TCPTP. Mutations and genetic variants of some genes in the TCPTP pathway are associated with lung cancer risk and survival. In the present study, we first investigated associations of 5,162 single nucleotide polymorphisms (SNPs) in 43 genes of this TCPTP pathway with lung cancer risk by using summary data of six published genome-wide association studies (GWAS) of 12,160 cases and 16,838 controls. We identified 11 independent SNPs in eight genes after correction for multiple comparisons by a false discovery rate <0.20. Then, we performed in silico functional analyses for these 11 SNPs by eQTL analysis, two of which, PTPN2 SNPs rs2847297 and rs2847282, were chosen as tagSNPs. We further included two additional GWAS datasets of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls), and the overall effects of these two SNPs among all eight GWAS studies remained significant (OR = 0.95, 95% CI = 0.92-0.98, and P = 0.004 for rs2847297; OR = 0.95, 95% CI = 0.92-0.99, and P = 0.009 for rs2847282). In conclusion, the PTPN2 rs2847297 and rs2847282 may be potential susceptible loci for lung cancer risk..
Li, N., Johnson, D.C., Weinhold, N., Kimber, S., Dobbins, S.E., Mitchell, J.S., Kinnersley, B., Sud, A., Law, P.J., Orlando, G., et al. (2017). Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism. Cell rep, Vol.20 (11), pp. 2556-2564. show abstract
Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15..
Liu, N.Q., Ter Huurne, M., Nguyen, L.N., Peng, T., Wang, S.-., Studd, J.B., Joshi, O., Ongen, H., Bramsen, J.B., Yan, J., et al. (2017). The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression. Nat commun, Vol.8, p. 14418. show abstract
Genome-wide association studies have identified a great number of non-coding risk variants for colorectal cancer (CRC). To date, the majority of these variants have not been functionally studied. Identification of allele-specific transcription factor (TF) binding is of great importance to understand regulatory consequences of such variants. A recently developed proteome-wide analysis of disease-associated SNPs (PWAS) enables identification of TF-DNA interactions in an unbiased manner. Here we perform a large-scale PWAS study to comprehensively characterize TF-binding landscape that is associated with CRC, which identifies 731 allele-specific TF binding at 116 CRC risk loci. This screen identifies the A-allele of rs1800734 within the promoter region of MLH1 as perturbing the binding of TFAP4 and consequently increasing DCLK3 expression through a long-range interaction, which promotes cancer malignancy through enhancing expression of the genes related to epithelial-to-mesenchymal transition..
Rodriguez-Broadbent, H., Law, P.J., Sud, A., Palin, K., Tuupanen, S., Gylfe, A., Hänninen, U.A., Cajuso, T., Tanskanen, T., Kondelin, J., et al. (2017). Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer. Int j cancer, Vol.140 (12), pp. 2701-2708. show abstract
While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 × 10-4 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia..
Went, M., Sud, A., Law, P.J., Johnson, D.C., Weinhold, N., Försti, A., van Duin, M., Mitchell, J.S., Chen, B., Kuiper, R., et al. (2017). Assessing the effect of obesity-related traits on multiple myeloma using a Mendelian randomisation approach. Blood cancer j, Vol.7 (6), p. e573.
Law, P.J., Sud, A., Mitchell, J.S., Henrion, M., Orlando, G., Lenive, O., Broderick, P., Speedy, H.E., Johnson, D.C., Kaiser, M., et al. (2017). Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci. Sci rep, Vol.7, p. 41071. show abstract
B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10-9) with opposing effects between CLL (P = 1.97 × 10-8) and HL (P = 3.31 × 10-3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10-12) was associated with increased CLL and HL risk (P = 4.68 × 10-12), and reduced MM risk (P = 1.12 × 10-2), and Gly70 in HLA-DQB1 (P = 3.15 × 10-10) showed opposing effects between CLL (P = 3.52 × 10-3) and HL (P = 3.41 × 10-9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs..
Wang, Y., McKay, J.D., Rafnar, T., Wang, Z., Timofeeva, M.N., Broderick, P., Zong, X., Laplana, M., Wei, Y., Han, Y., et al. (2017). Corrigendum: Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nat genet, Vol.49 (4), p. 651.
Scales, M., Chubb, D., Dobbins, S.E., Johnson, D.C., Li, N., Sternberg, M.J., Weinhold, N., Stein, C., Jackson, G., Davies, F.E., et al. (2017). Search for rare protein altering variants influencing susceptibility to multiple myeloma. Oncotarget, Vol.8 (22), pp. 36203-36210. show abstract
The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both single variant and gene burden tests. We did not identify any recurrent coding low-frequency alleles (1-5%) with moderate effect that were statistically associated with MM. In a gene burden analysis we did however identify a promising relationship between variation in the marrow kinetochore microtubule stromal gene KIF18A, which plays a role in control mitotic chromosome positioning dynamics, and risk of MM (P =3.6x10-6). Further analysis showed KIF18A displays a distinct pattern of expression across molecular subgroups of MM as well as being associated with patient survival. Our results inform future study design and provide a resource for contextualizing the impact of candidate MM susceptibility genes..
Bolton, K.L., Tyrer, J., Song, H., Ramus, S.J., Notaridou, M., Jones, C., Sher, T., Gentry-Maharaj, A., Wozniak, E., Tsai, Y.-., et al. (2016). Common variants at 19p13 are associated with susceptibility to ovarian cancer (vol 42, pg 880, 2010). Nature genetics, Vol.48 (1), pp. 101-101.
Bolton, K.L., Tyrer, J., Song, H., Ramus, S.J., Notaridou, M., Jones, C., Sher, T., Gentry-Maharaj, A., Wozniak, E., Tsai, Y.-., et al. (2016). Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat genet, Vol.48 (1), p. 101.
Fehringer, G., Kraft, P., Pharoah, P.D., Eeles, R.A., Chatterjee, N., Schumacher, F.R., Schildkraut, J.M., Lindström, S., Brennan, P., Bickeböller, H., et al. (2016). Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations. Cancer res, Vol.76 (17), pp. 5103-5114. show abstract
Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR..
Mitchell, J.S., Li, N., Weinhold, N., Försti, A., Ali, M., van Duin, M., Thorleifsson, G., Johnson, D.C., Chen, B., Halvarsson, B.-., et al. (2016). Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nat commun, Vol.7, p. 12050. show abstract
Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10(-8)), 6q21 (rs9372120, P=9.09 × 10(-15)), 7q36.1 (rs7781265, P=9.71 × 10(-9)), 8q24.21 (rs1948915, P=4.20 × 10(-11)), 9p21.3 (rs2811710, P=1.72 × 10(-13)), 10p12.1 (rs2790457, P=1.77 × 10(-8)), 16q23.1 (rs7193541, P=5.00 × 10(-12)) and 20q13.13 (rs6066835, P=1.36 × 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development..
Orlando, G., Law, P.J., Palin, K., Tuupanen, S., Gylfe, A., Hänninen, U.A., Cajuso, T., Tanskanen, T., Kondelin, J., Kaasinen, E., et al. (2016). Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease. Hum mol genet, Vol.25 (11), pp. 2349-2359. show abstract
To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10-8, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2 = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD..
Amirian, E.S., Zhou, R., Wrensch, M.R., Olson, S.H., Scheurer, M.E., Il'yasova, D., Lachance, D., Armstrong, G.N., McCoy, L.S., Lau, C.C., et al. (2016). Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study. Cancer epidemiol biomarkers prev, Vol.25 (2), pp. 282-290. show abstract
BACKGROUND: Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk. METHODS: The GICC contains detailed information on history of atopic conditions for 4,533 cases and 4,171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis ORs, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema. RESULTS: Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared with not having respiratory allergies (mOR, 0.72; 95% confidence interval, 0.58-0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma. CONCLUSION: A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental. IMPACT: As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biologic mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention..
Frampton, M.J., Law, P., Litchfield, K., Morris, E.J., Kerr, D., Turnbull, C., Tomlinson, I.P. & Houlston, R.S. (2016). Implications of polygenic risk for personalised colorectal cancer screening. Ann oncol, Vol.27 (3), pp. 429-434. show abstract
BACKGROUND: We modelled the utility of applying a personalised screening approach for colorectal cancer (CRC) when compared with standard age-based screening. In this personalised screening approach, eligibility is determined by absolute risk which is calculated from age and polygenic risk score (PRS), where the PRS is relative risk attributable to common genetic variation. In contrast, eligibility in age-based screening is determined only by age. DESIGN: We calculated absolute risks of CRC from UK population age structure, incidence and mortality rate data, and a PRS distribution which we derived for the 37 known CRC susceptibility variants. We compared the number of CRC cases potentially detectable by personalised and age-based screening. Using Genome-Wide Complex Trait Analysis to calculate the heritability attributable to common variation, we repeated the analysis assuming all common CRC risk variants were known. RESULTS: Based on the known CRC variants, individuals with a PRS in the top 1% have a 2.9-fold increased CRC risk over the population median. Compared with age-based screening (aged 60: 10-year absolute risk 1.96% in men, 1.19% in women, as per the UK NHS National Bowel Screening Programme), personalised screening of individuals aged 55-69 at the same risk would lead to 16% fewer men and 17% fewer women being eligible for screening with 10% and 8%, respectively, fewer screen-detected cases. If all susceptibility variants were known, individuals with a PRS in the top 1% would have an estimated 7.7-fold increased risk. Personalised screening would then result in 26% fewer men and women being eligible for screening with 7% and 5% fewer screen-detected cases. CONCLUSION: Personalised screening using PRS has the potential to optimise population screening for CRC and to define those likely to maximally benefit from chemoprevention. There are however significant technical and operational details to be addressed before any such programme is introduced..
Kang, X., Liu, H., Onaitis, M.W., Liu, Z., Owzar, K., Han, Y., Su, L., Wei, Y., Hung, R.J., Brhane, Y., et al. (2016). Polymorphisms of the centrosomal gene (FGFR1OP) and lung cancer risk: a meta-analysis of 14,463 cases and 44,188 controls. Carcinogenesis, Vol.37 (3), pp. 280-289. show abstract
Centrosome abnormalities are often observed in premalignant lesions and in situ tumors and have been associated with aneuploidy and tumor development. We investigated the associations of 9354 single-nucleotide polymorphisms (SNPs) in 106 centrosomal genes with lung cancer risk by first using the summary data from six published genome-wide association studies (GWASs) of the Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16 838 controls) and then conducted in silico replication in two additional independent lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1319 cases and 26,380 controls). A total of 44 significant SNPs with false discovery rate (FDR) ≤ 0.05 were mapped to one novel gene FGFR1OP and two previously reported genes (TUBB and BRCA2). After combined the results from TRICL with those from Harvard and deCODE, the most significant association (P combined = 8.032 × 10(-6)) was with rs151606 within FGFR1OP. The rs151606 T>G was associated with an increased risk of lung cancer [odds ratio (OR) = 1.10, 95% confidence interval (95% CI) = 1.05-1.14]. Another significant tagSNP rs12212247 T>C (P combined = 9.589 × 10(-6)) was associated with a decreased risk of lung cancer (OR = 0.93, 95% CI = 0.90-0.96). Further in silico functional analyzes revealed that rs151606 might affect transcriptional regulation and result in decreased FGFR1OP expression (P trend = 0.022). The findings shed some new light on the role of centrosome abnormalities in the susceptibility to lung carcinogenesis..
Johnson, D.C., Weinhold, N., Mitchell, J., Chen, B., Stephens, O.W., Försti, A., Nickel, J., Kaiser, M., Gregory, W.A., Cairns, D., et al. (2016). Genetic factors influencing the risk of multiple myeloma bone disease. Leukemia, Vol.30 (4), pp. 883-888. show abstract
A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totaling 3774), which had been radiologically surveyed for MBD. Each patient had been genotyped for ~6 00 000 single-nucleotide polymorphisms with genotypes for six million common variants imputed using 1000 Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio=1.38, P=4.09 × 10(-9)) and a promising association at 19q13.43 (rs74676832, odds ratio=1.97, P=9.33 × 10(-7)). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM. .
Kinnersley, B., Kamatani, Y., Labussière, M., Wang, Y., Galan, P., Mokhtari, K., Delattre, J.-., Gousias, K., Schramm, J., Schoemaker, M.J., et al. (2016). Search for new loci and low-frequency variants influencing glioma risk by exome-array analysis. Eur j hum genet, Vol.24 (5), pp. 717-724. show abstract
To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10(-49)); however, these variants which are most likely to impact on risk, are rare (MAF<5%). Although no single variant showed an association which was statistically significant at the genome-wide threshold a number represented promising associations - BRCA2:c.9976A>T, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10(-4) for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10(-3), for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10(-6)). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power. .
Cheng, T.H., Thompson, D.J., O'Mara, T.A., Painter, J.N., Glubb, D.M., Flach, S., Lewis, A., French, J.D., Freeman-Mills, L., Church, D., et al. (2016). Five endometrial cancer risk loci identified through genome-wide association analysis. Nat genet, Vol.48 (6), pp. 667-674. show abstract
We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer..
Yuan, H., Liu, H., Liu, Z., Owzar, K., Han, Y., Su, L., Wei, Y., Hung, R.J., McLaughlin, J., Brhane, Y., et al. (2016). A Novel Genetic Variant in Long Non-coding RNA Gene NEXN-AS1 is Associated with Risk of Lung Cancer. Sci rep, Vol.6, p. 34234. show abstract
Lung cancer etiology is multifactorial, and growing evidence has indicated that long non-coding RNAs (lncRNAs) are important players in lung carcinogenesis. We performed a large-scale meta-analysis of 690,564 SNPs in 15,531 autosomal lncRNAs by using datasets from six previously published genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium in populations of European ancestry. Previously unreported significant SNPs (P value < 1 × 10-7) were further validated in two additional independent lung cancer GWAS datasets from Harvard University and deCODE. In the final meta-analysis of all eight GWAS datasets with 17,153 cases and 239,337 controls, a novel risk SNP rs114020893 in the lncRNA NEXN-AS1 region at 1p31.1 remained statistically significant (odds ratio = 1.17; 95% confidence interval = 1.11-1.24; P = 8.31 × 10-9). In further in silico analysis, rs114020893 was predicted to change the secondary structure of the lncRNA. Our finding indicates that SNP rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility..
Johnson, D.C., Weinhold, N., Mitchell, J.S., Chen, B., Kaiser, M., Begum, D.B., Hillengass, J., Bertsch, U., Gregory, W.A., Cairns, D., et al. (2016). Genome-wide association study identifies variation at 6q25 1 associated with survival in multiple myeloma. Nat commun, Vol.7, p. 10290. show abstract
Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to identify genetic markers associated with MM overall survival (MM-OS), we conduct a meta-analysis of four patient series of European ancestry, totalling 3,256 patients with 1,200 MM-associated deaths. Each series is genotyped for ∼600,000 single nucleotide polymorphisms across the genome; genotypes for six million common variants are imputed using 1000 Genomes Project and UK10K as the reference. The association between genotype and OS is assessed by Cox proportional hazards model adjusting for age, sex, International staging system and treatment. We identify a locus at 6q25.1 marked by rs12374648 associated with MM-OS (hazard ratio=1.34, 95% confidence interval=1.22-1.48, P=4.69 × 10(-9)). Our findings have potential clinical implications since they demonstrate that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors. .
Dobbins, S.E., Broderick, P., Chubb, D., Kinnersley, B., Sherborne, A.L. & Houlston, R.S. (2016). Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes. Fam cancer, Vol.15 (4), pp. 593-599. show abstract
Although family history is a major risk factor for colorectal cancer (CRC) a genetic diagnosis cannot be obtained in over 50 % of familial cases when screened for known CRC cancer susceptibility genes. The genetics of undefined-familial CRC is complex and recent studies have implied additional clinically actionable mutations for CRC in susceptibility genes for other cancers. To clarify the contribution of non-CRC susceptibility genes to undefined-familial CRC we conducted a mutational screen of 114 cancer susceptibility genes in 847 patients with early-onset undefined-familial CRC and 1609 controls by analysing high-coverage exome sequencing data. We implemented American College of Medical Genetics and Genomics standards and guidelines for assigning pathogenicity to variants. Globally across all 114 cancer susceptibility genes no statistically significant enrichment of likely pathogenic variants was shown (6.7 % cases 57/847, 5.3 % controls 85/1609; P = 0.15). Moreover there was no significant enrichment of mutations in genes such as TP53 or BRCA2 which have been proposed for clinical testing in CRC. In conclusion, while we identified genes that may be considered interesting candidates as determinants of CRC risk warranting further research, there is currently scant evidence to support a role for genes other than those responsible for established CRC syndromes in the clinical management of familial CRC..
Speedy, H.E., Kinnersley, B., Chubb, D., Broderick, P., Law, P.J., Litchfield, K., Jayne, S., Dyer, M.J., Dearden, C., Follows, G.A., et al. (2016). Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia. Blood, Vol.128 (19), pp. 2319-2326. show abstract
Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P = .009). This study further highlights telomere dysregulation as a key process in CLL development..
Kinnersley, B., Chubb, D., Dobbins, S.E., Frampton, M., Buch, S., Timofeeva, M.N., Castellví-Bel, S., Farrington, S.M., Forsti, A., Hampe, J., et al. (2016). Correspondence: SEMA4A variation and risk of colorectal cancer. Nat commun, Vol.7, p. 10611.
Zuber, V., Marconett, C.N., Shi, J., Hua, X., Wheeler, W., Yang, C., Song, L., Dale, A.M., Laplana, M., Risch, A., et al. (2016). Pleiotropic Analysis of Lung Cancer and Blood Triglycerides. J natl cancer inst, Vol.108 (12). show abstract
Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10(-6)) and blood triglycerides (P = 1.39x10(-5)). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 × 10(-4)) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21 ,: Pcombined = 5.20x10(-9)). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer..
Jarvis, D., Mitchell, J.S., Law, P.J., Palin, K., Tuupanen, S., Gylfe, A., Hänninen, U.A., Cajuso, T., Tanskanen, T., Kondelin, J., et al. (2016). Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer. Br j cancer, Vol.115 (2), pp. 266-272. show abstract
BACKGROUND: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC. METHODS: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls. RESULTS: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P=0.033), 1.59 (95% CI: 1.08-2.34, P=0.019) and 1.07 (95% CI: 1.03-1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89-1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P=7.7 × 10(-4)) and 1.40 (95% CI: 1.14-1.72, P=1.2 × 10(-3)), respectively. CONCLUSIONS: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity..
Karami, S., Han, Y., Pande, M., Cheng, I., Rudd, J., Pierce, B.L., Nutter, E.L., Schumacher, F.R., Kote-Jarai, Z., Lindstrom, S., et al. (2016). Telomere structure and maintenance gene variants and risk of five cancer types. Int j cancer, Vol.139 (12), pp. 2655-2670. show abstract
Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk..
Johnson, N., De Ieso, P., Migliorini, G., Orr, N., Broderick, P., Catovsky, D., Matakidou, A., Eisen, T., Goldsmith, C., Dudbridge, F., et al. (2016). Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer. Cancer res, Vol.76 (6), pp. 1485-1493. show abstract
CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers..
Amirian, E.S., Armstrong, G.N., Zhou, R., Lau, C.C., Claus, E.B., Barnholtz-Sloan, J.S., Il'yasova, D., Schildkraut, J., Ali-Osman, F., Sadetzki, S., et al. (2016). The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium. Am j epidemiol, Vol.183 (2), pp. 85-91. show abstract
Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions. .
Litchfield, K., Levy, M., Dudakia, D., Proszek, P., Shipley, C., Basten, S., Rapley, E., Bishop, D.T., Reid, A., Huddart, R., et al. (2016). Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility. Nat commun, Vol.7, p. 13840. show abstract
Testicular germ cell tumour (TGCT) is the most common cancer in young men. Here we sought to identify risk factors for TGCT by performing whole-exome sequencing on 328 TGCT cases from 153 families, 634 sporadic TGCT cases and 1,644 controls. We search for genes that are recurrently affected by rare variants (minor allele frequency <0.01) with potentially damaging effects and evidence of segregation in families. A total of 8.7% of TGCT families carry rare disruptive mutations in the cilia-microtubule genes (CMG) as compared with 0.5% of controls (P=2.1 × 10-8). The most significantly mutated CMG is DNAAF1 with biallelic inactivation and loss of DNAAF1 expression shown in tumours from carriers. DNAAF1 mutation as a cause of TGCT is supported by a dnaaf1hu255h(+/-) zebrafish model, which has a 94% risk of TGCT. Our data implicate cilia-microtubule inactivation as a cause of TGCT and provide evidence for CMGs as cancer susceptibility genes..
Chubb, D., Broderick, P., Dobbins, S.E., Frampton, M., Kinnersley, B., Penegar, S., Price, A., Ma, Y.P., Sherborne, A.L., Palles, C., et al. (2016). Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. Nat commun, Vol.7, p. 11883. show abstract
Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1-5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes..
Kandaswamy, R., Sava, G.P., Speedy, H.E., Beà, S., Martín-Subero, J.I., Studd, J.B., Migliorini, G., Law, P.J., Puente, X.S., Martín-García, D., et al. (2016). Genetic Predisposition to Chronic Lymphocytic Leukemia Is Mediated by a BMF Super-Enhancer Polymorphism. Cell rep, Vol.16 (8), pp. 2061-2067. show abstract
Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10(-13), odds ratio = 1.35), localizes to a super-enhancer defined by extensive histone H3 lysine 27 acetylation in intron 3 of B cell lymphoma 2 (BCL2)-modifying factor (BMF). The rs539846-A risk allele alters a conserved RELA-binding motif, disrupts RELA binding, and is associated with decreased BMF expression in CLL. These findings are consistent with rs539846 influencing CLL susceptibility through differential RELA binding, with direct modulation of BMF expression impacting on anti-apoptotic BCL2, a hallmark of oncogenic dependency in CLL..
Li, N., Johnson, D.C., Weinhold, N., Studd, J.B., Orlando, G., Mirabella, F., Mitchell, J.S., Meissner, T., Kaiser, M., Goldschmidt, H., et al. (2016). Multiple myeloma risk variant at 7p15 3 creates an IRF4-binding site and interferes with CDCA7L expression. Nat commun, Vol.7, p. 13656. show abstract
Genome-wide association studies have identified several risk loci for multiple myeloma (MM); however, the mechanisms by which they influence MM are unknown. Here by using genetic association data and functional characterization, we demonstrate that rs4487645 G>T, the most highly associated variant (P = 5.30 × 10-25), resides in an enhancer element 47 kb upstream of the transcription start site of c-Myc-interacting CDCA7L. The G-risk allele, associated with increased CDCA7L expression (P=1.95 × 10-36), increases IRF4 binding and the enhancer interacts with the CDCA7L promoter. We show that suppression of CDCA7L limits MM proliferation through apoptosis, and increased CDCA7L expression is associated with adverse patient survival. These findings implicate IRF4-mediated CDCA7L expression in MM biology and indicate how germline variation might confer susceptibility to MM..
Chubb, D., Broderick, P., Dobbins, S.E. & Houlston, R.S. (2016). CanVar: A resource for sharing germline variation in cancer patients. F1000res, Vol.5, p. 2813. show abstract
The advent of high-throughput sequencing has accelerated our ability to discover genes predisposing to disease and is transforming clinical genomic sequencing. In both contexts knowledge of the spectrum and frequency of genetic variation in the general population and in disease cohorts is vital to the interpretation of sequencing data. While population level data is becoming increasingly available from publicly accessible sources, as exemplified by The Exome Aggregation Consortium (ExAC), the availability of large-scale disease-specific frequency information is limited. These data are of particular importance to contextualise findings from clinical mutation screens and small gene discovery projects. This is especially true for cancer, which is typified by a number of hereditary predisposition syndromes. Although mutation frequencies in tumours are available from resources such as Cosmic and The Cancer Genome Atlas, a similar facility for germline variation is lacking. Here we present the Cancer Variation Resource (CanVar) an online database which has been developed using the ExAC framework to provide open access to germline variant frequency data from the sequenced exomes of cancer patients. In its first release, CanVar catalogues the exomes of 1,006 familial early-onset colorectal cancer (CRC) patients sequenced at The Institute of Cancer Research. It is anticipated that CanVar will host data for additional cancers, providing a resource for others studying cancer predisposition and an example of how the research community can utilise the ExAC framework to share sequencing data..
Cheng, T.H., Thompson, D., Painter, J., O'Mara, T., Gorman, M., Martin, L., Palles, C., Jones, A., Buchanan, D.D., Win, A.K., et al. (2015). Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1. Sci rep, Vol.5, p. 17369. show abstract
High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers..
Kinnersley, B., Labussière, M., Holroyd, A., Di Stefano, A.-., Broderick, P., Vijayakrishnan, J., Mokhtari, K., Delattre, J.-., Gousias, K., Schramm, J., et al. (2015). Genome-wide association study identifies multiple susceptibility loci for glioma. Nat commun, Vol.6, p. 8559. show abstract
Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10(-9)) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10(-8)), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10(-11)), 12q21.2 (rs12230172, P=7.53 × 10(-11)) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10(-9)). Our findings provide further insights into the genetic basis of the different glioma subtypes. .
Ware, J.J., Aveyard, P., Broderick, P., Houlston, R.S., Eisen, T. & Munafò, M.R. (2015). The association of rs1051730 genotype on adherence to and consumption of prescribed nicotine replacement therapy dose during a smoking cessation attempt. Drug alcohol depend, Vol.151, pp. 236-240. show abstract
INTRODUCTION: While nicotine replacement therapy (NRT) is an effective pharmacological smoking cessation treatment, its efficacy is influenced by adherence to and consumption of the prescribed dose. The genetic variant rs1051730 in the nicotinic receptor gene cluster CHRNA5-A3-B4 influences smoking quantity. The aim of this study was to explore the impact of rs1051730 genotype on adherence to and consumption of NRT prescription following a smoking cessation attempt. METHODS: Secondary analysis of data from a pharmacogenetic smoking cessation trial. Participants (n = 448) were prescribed a daily dose of NRT for four weeks post quit attempt, and monitored during weekly clinic visits. Outcome measures were NRT prescription adherence rate (%) and average daily NRT consumption (mg) at 7- and 28-days after the quit attempt. RESULTS: An association between rs1051730 genotype and both outcome measures was observed at 7-days after the quit date. Each copy of the minor allele corresponded to a 2.9% decrease in adherence to prescribed NRT dose (P = 0.044), and a 1.0mg decrease in daily NRT consumption (P = 0.026). Adjusting for number of cigarettes smoked during this period only slightly attenuated these associations. There was no clear statistical evidence of an association between genotype and adherence or consumption at 28-days. CONCLUSIONS: This is the first study to evaluate the impact of rs1051730 genotype on consumption of and adherence to NRT prescription during a smoking cessation attempt. We observed an association between this variant and both outcome measures at 7-days; however, this was only moderate. These findings require replication in an independent sample..
Galvan, A., Colombo, F., Frullanti, E., Dassano, A., Noci, S., Wang, Y., Eisen, T., Matakidou, A., Tomasello, L., Vezzalini, M., et al. (2015). Germline polymorphisms and survival of lung adenocarcinoma patients: a genome-wide study in two European patient series. Int j cancer, Vol.136 (5), pp. E262-E271. show abstract
In lung cancer, the survival of patients with the same clinical stage varies widely for unknown reasons. In this two-phase study, we examined the hypothesis that germline variations influence the survival of patients with lung adenocarcinoma. First, we analyzed existing genotype and clinical data from 289 UK-resident patients with lung adenocarcinoma, identifying 86 single nucleotide polymorphisms (SNPs) that associated with survival (p < 0.01). We then genotyped these candidate SNPs in a validation series of 748 patients from Italy that resulted genetically compatible with the UK series based on principal component analysis. In a Cox proportional hazard model adjusted for age, sex and clinical stage, four SNPs were confirmed on the basis of their having a hazard ratio (HR) indicating the same direction of effect in the two series and p < 0.05. The strongest association was provided by rs2107561, an intronic SNP of PTPRG, protein tyrosine phosphatase, receptor type, G; the C allele was associated with poorer survival in both patient series (pooled analysis loge HR = 0.31; 95% CI: 0.15-0.46, p = 8.5 × 10(-5) ). PTPRG mRNA levels in 43 samples of lung adenocarcinoma were 40% of those observed in noninvolved lung tissue from the same patients. PTPRG overexpression significantly inhibited the clonogenicity of A549 lung carcinoma cells and the anchorage-independent growth of the NCI-H460 large cell lung cancer line. These four germline variants represent promising candidates that, with further study, may help predict clinical outcome. In addition, the PTPRG locus may have a role in tumor progression..
Bainbridge, M.N., Armstrong, G.N., Gramatges, M.M., Bertuch, A.A., Jhangiani, S.N., Doddapaneni, H., Lewis, L., Tombrello, J., Tsavachidis, S., Liu, Y., et al. (2015). Germline mutations in shelterin complex genes are associated with familial glioma. J natl cancer inst, Vol.107 (1), p. 384. show abstract
Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma. .
Kinnersley, B., Mitchell, J.S., Gousias, K., Schramm, J., Idbaih, A., Labussière, M., Marie, Y., Rahimian, A., Wichmann, H.-., Schreiber, S., et al. (2015). Quantifying the heritability of glioma using genome-wide complex trait analysis. Sci rep, Vol.5, p. 17267. show abstract
Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing glioma risk. While these SNPs only explain a small proportion of the genetic risk it is unclear how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we applied Genome-Wide Complex Trait Analysis (GCTA) to three GWAS datasets totalling 3,373 cases and 4,571 controls and performed a meta-analysis to estimate the heritability of glioma. Our results identify heritability estimates of 25% (95% CI: 20-31%, P = 1.15 × 10(-17)) for all forms of glioma - 26% (95% CI: 17-35%, P = 1.05 × 10(-8)) for glioblastoma multiforme (GBM) and 25% (95% CI: 17-32%, P = 1.26 × 10(-10)) for non-GBM tumors. This is a substantial increase from the genetic variance identified by the currently identified GWAS risk loci (~6% of common heritability), indicating that most of the heritable risk attributable to common genetic variants remains to be identified..
Al-Tassan, N.A., Whiffin, N., Hosking, F.J., Palles, C., Farrington, S.M., Dobbins, S.E., Harris, R., Gorman, M., Tenesa, A., Meyer, B.F., et al. (2015). Erratum: A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer. Sci rep, Vol.5, p. 12372.
Bartram, T., Burkhardt, B., Wössmann, W., Seidemann, K., Zimmermann, M., Cario, G., Lisfeld, J., Ellinghaus, E., Franke, A., Houlston, R.S., et al. (2015). Childhood acute lymphoblastic leukemia-associated risk-loci IKZF1, ARID5B and CEBPE and risk of pediatric non-Hodgkin lymphoma: a report from the Berlin-Frankfurt-Münster Study Group. Leuk lymphoma, Vol.56 (3), pp. 814-816.
Weinhold, N., Meissner, T., Johnson, D.C., Seckinger, A., Moreaux, J., Försti, A., Chen, B., Nickel, J., Chubb, D., Rawstron, A.C., et al. (2015). The 7p15 3 (rs4487645) association for multiple myeloma shows strong allele-specific regulation of the MYC-interacting gene CDCA7L in malignant plasma cells. Haematologica, Vol.100 (3), pp. e110-e113.
Sava, G.P., Speedy, H.E., Di Bernardo, M.C., Dyer, M.J., Holroyd, A., Sunter, N.J., Marr, H., Mansouri, L., Deaglio, S., Karabon, L., et al. (2015). Common variation at 12q24 13 (OAS3) influences chronic lymphocytic leukemia risk. Leukemia, Vol.29 (3), pp. 748-751.
Interleukin 1 Genetics Consortium, (2015). Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis. Lancet diabetes endocrinol, Vol.3 (4), pp. 243-253. show abstract
BACKGROUND: To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. METHODS: We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453,411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746,171 total participants). FINDINGS: For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p = 9.3 × 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1.7%; p = 3.5 × 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p = 7.7 × 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p = 1.8 × 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p = 3.9 × 10(-10)). Per-allele odds ratios were 0.97 (0.95-0.99; p = 9.9 × 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p = 0.47) for type 2 diabetes, 1.00 (0.98-1.02; p = 0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p = 1.8 × 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. INTERPRETATION: Human genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations..
Jalali, A., Amirian, E.S., Bainbridge, M.N., Armstrong, G.N., Liu, Y., Tsavachidis, S., Jhangiani, S.N., Plon, S.E., Lau, C.C., Claus, E.B., et al. (2015). Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene Consortium. Sci rep, Vol.5, p. 8278. show abstract
Glioma is a rare, but highly fatal, cancer that accounts for the majority of malignant primary brain tumors. Inherited predisposition to glioma has been consistently observed within non-syndromic families. Our previous studies, which involved non-parametric and parametric linkage analyses, both yielded significant linkage peaks on chromosome 17q. Here, we use data from next generation and Sanger sequencing to identify familial glioma candidate genes and variants on chromosome 17q for further investigation. We applied a filtering schema to narrow the original list of 4830 annotated variants down to 21 very rare (<0.1% frequency), non-synonymous variants. Our findings implicate the MYO19 and KIF18B genes and rare variants in SPAG9 and RUNDC1 as candidates worthy of further investigation. Burden testing and functional studies are planned. .
Litchfield, K., Thomsen, H., Mitchell, J.S., Sundquist, J., Houlston, R.S., Hemminki, K. & Turnbull, C. (2015). Quantifying the heritability of testicular germ cell tumour using both population-based and genomic approaches. Sci rep, Vol.5, p. 13889. show abstract
A sizable fraction of testicular germ cell tumour (TGCT) risk is expected to be explained by heritable factors. Recent genome-wide association studies (GWAS) have successfully identified a number of common SNPs associated with TGCT. It is however, unclear how much common variation there is left to be accounted for by other, yet to be identified, common SNPs and what contribution common genetic variation makes to the heritable risk of TGCT. We approached this question using two complimentary analytical techniques. We undertook a population-based analysis of the Swedish family-cancer database, through which we estimated that the heritability of TGCT at 48.9% (CI:47.2%-52.3%). We also applied Genome-Wide Complex Trait Analysis to 922 cases and 4,842 controls to estimate the heritability of TGCT. The heritability explained by known common risk SNPs identified by GWAS was 9.1%, whereas the heritability explained by all common SNPs was 37.4% (CI:27.6%-47.2%). These complementary findings indicate that the known TGCT SNPs only explain a small proportion of the heritability and many additional common SNPs remain to be identified. The data also suggests that a fraction of the heritability of TGCT is likely to be explained by other classes of genetic variation, such as rare disease-causing alleles. .
Timofeeva, M.N., Kinnersley, B., Farrington, S.M., Whiffin, N., Palles, C., Svinti, V., Lloyd, A., Gorman, M., Ooi, L.-., Hosking, F., et al. (2015). Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer. Sci rep, Vol.5, p. 16286. show abstract
Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10(-7)), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10(-7)); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10(-7) and OR = 1.09, P = 7.4 × 10(-8)); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10(-9)), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P < 2.90 × 10(-6)). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10(-4)) and DNA mismatch repair genes (P = 6.1 × 10(-4)) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC. .
Chubb, D., Broderick, P., Frampton, M., Kinnersley, B., Sherborne, A., Penegar, S., Lloyd, A., Ma, Y.P., Dobbins, S.E. & Houlston, R.S., et al. (2015). Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. J clin oncol, Vol.33 (5), pp. 426-432. show abstract
PURPOSE: Knowledge of the contribution of high-penetrance susceptibility to familial colorectal cancer (CRC) is relevant to the counseling, treatment, and surveillance of CRC patients and families. PATIENTS AND METHODS: To quantify the impact of germline mutation to familial CRC, we sequenced the mismatch repair genes (MMR) APC, MUTYH, and SMAD4/BMPR1A in 626 early-onset familial CRC cases ascertained through a population-based United Kingdom national registry. In addition, we evaluated the contribution of mutations in the exonuclease domain (exodom) of POLE and POLD1 genes that have recently been reported to confer CRC risk. RESULTS: Overall mutations (pathogenic, likely pathogenic) in MMR genes make the highest contribution to familial CRC (10.9%). Mutations in the other established CRC genes account for 3.3% of cases. POLE/POLD1 exodom mutations were identified in three patients with family histories consistent with dominant transmission of CRC. Collectively, mutations in the known genes account for 14.2% of familial CRC (89 of 626 cases; 95% CI = 11.5, 17.2). CONCLUSION: A genetic diagnosis is feasible in a high proportion of familial CRC. Mainstreaming such analysis in clinical practice should enable the medical management of patients and their families to be optimized. Findings suggest CRC screening of POLE and POLD1 mutation carriers should be comparable to that afforded to those at risk of HNPCC. Although the risk of CRC associated with unexplained familial CRC is in general moderate, in some families the risk is substantive and likely to be the consequence of unidentified genes, as exemplified by POLE and POLD1. Our findings have utility in the design of genetic analyses to identify such novel CRC risk genes..
Hung, R.J., Ulrich, C.M., Goode, E.L., Brhane, Y., Muir, K., Chan, A.T., Marchand, L.L., Schildkraut, J., Witte, J.S., Eeles, R., et al. (2015). Cross Cancer Genomic Investigation of Inflammation Pathway for Five Common Cancers: Lung, Ovary, Prostate, Breast, and Colorectal Cancer. J natl cancer inst, Vol.107 (11). show abstract
BACKGROUND: Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted. METHODS: We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided. RESULTS: We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10(-8), and it showed an association with lung cancer (P = 2.01 x 10(-6)), colorectal cancer (GECCO P = 6.72x10(-6); CORECT P = 3.32x10(-5)), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10(-6)), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003). CONCLUSIONS: Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer..
Brenner, D.R., Amos, C.I., Brhane, Y., Timofeeva, M.N., Caporaso, N., Wang, Y., Christiani, D.C., Bickeböller, H., Yang, P., Albanes, D., et al. (2015). Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia. Carcinogenesis, Vol.36 (11), pp. 1314-1326. show abstract
Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range. .
Labreche, K., Simeonova, I., Kamoun, A., Gleize, V., Chubb, D., Letouzé, E., Riazalhosseini, Y., Dobbins, S.E., Elarouci, N., Ducray, F., et al. (2015). TCF12 is mutated in anaplastic oligodendroglioma. Nat commun, Vol.6, p. 7207. show abstract
Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO. .
Wang, Y., Wei, Y., Gaborieau, V., Shi, J., Han, Y., Timofeeva, M.N., Su, L., Li, Y., Eisen, T., Amos, C.I., et al. (2015). Deciphering associations for lung cancer risk through imputation and analysis of 12,316 cases and 16,831 controls. Eur j hum genet, Vol.23 (12), pp. 1723-1728. show abstract
Recent genome-wide association studies have identified common variants at multiple loci influencing lung cancer risk. To decipher the genetic basis of the association signals at 3q28, 5p15.33, 6p21.33, 9p21 and 12p13.33, we performed a meta-analysis of data from five genome-wide association studies in populations of European ancestry totalling 12 316 lung cancer cases and 16 831 controls using imputation to recover untyped genotypes. For four of the regions, it was possible to refine the association signal identifying a smaller region of interest likely to harbour the functional variant. Our analysis did not provide evidence that any of the associations at the loci being a consequence of synthetic associations rather than linkage disequilibrium with a common risk variant at these risk loci. .
Vijayakrishnan, J., Henrion, M., Moorman, A.V., Fiege, B., Kumar, R., da Silva Filho, M.I., Holroyd, A., Koehler, R., Thomsen, H., Irving, J.A., et al. (2015). The 9p21 3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A. Sci rep, Vol.5, p. 15065. show abstract
Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio = 2.42, P = 3.45 × 10(-19)). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the CDKN2A transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm..
Zhang, C., Doherty, J.A., Burgess, S., Hung, R.J., Lindström, S., Kraft, P., Gong, J., Amos, C.I., Sellers, T.A., Monteiro, A.N., et al. (2015). Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study. Hum mol genet, Vol.24 (18), pp. 5356-5366. show abstract
Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. .
Litchfield, K., Mitchell, J.S., Shipley, J., Huddart, R., Rajpert-De Meyts, E., Skakkebæk, N.E., Houlston, R.S. & Turnbull, C. (2015). Polygenic susceptibility to testicular cancer: implications for personalised health care. Br j cancer, Vol.113 (10), pp. 1512-1518. show abstract
BACKGROUND: The increasing incidence of testicular germ cell tumour (TGCT) combined with its strong heritable basis suggests that stratified screening for the early detection of TGCT may be clinically useful. We modelled the efficiency of such a personalised screening approach, based on genetic risk profiling in combination with other diagnostic tools. METHODS: We compared the number of cases potentially detectable in the population under a number of screening models. The polygenic risk scoring (PRS) model was assumed to have a log-normal relative risk distribution across the 19 currently known TGCT susceptibility variants. The diagnostic performance of testicular biopsy and non-invasive semen analysis was also assessed, within a simulated combined screening programme. RESULTS: The area under the curve for the TGCT PRS model was 0.72 with individuals in the top 1% of the PRS having a nine-fold increased TGCT risk compared with the population median. Results from population-screening simulations only achieved a maximal positive predictive value (PPV) of 60%, highlighting broader clinical factors that challenge such strategies, not least the rare nature of TGCT. In terms of future improvements, heritability estimates suggest that a significant number of additional genetic risk factors for TGCT remain to be discovered, identification of which would potentially yield improvement of the PPV to 80-90%. CONCLUSIONS: While personalised screening models may offer enhanced TGCT risk discrimination, presently the case for population-level testing is not compelling. However, future advances, such as more routine generation of whole genome data is likely to alter the landscape. More targeted screening programs may plausibly then offer clinical benefit, particularly given the significant survivorship issues associated with the successful treatment of TGCT..
Jäger, R., Migliorini, G., Henrion, M., Kandaswamy, R., Speedy, H.E., Heindl, A., Whiffin, N., Carnicer, M.J., Broome, L., Dryden, N., et al. (2015). Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci. Nat commun, Vol.6, p. 6178. show abstract
Multiple regulatory elements distant from their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer-promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we develop a capture Hi-C (cHi-C) approach to allow an agnostic characterization of these physical interactions on a genome-wide scale. Single-nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci allows us to identify key long-range chromatin interactions in cis and trans involving these loci. .
Al-Tassan, N.A., Whiffin, N., Hosking, F.J., Palles, C., Farrington, S.M., Dobbins, S.E., Harris, R., Gorman, M., Tenesa, A., Meyer, B.F., et al. (2015). A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer. Sci rep, Vol.5, p. 10442. show abstract
Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10(-8), odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants. .
Sud, A., Cooke, R., Swerdlow, A.J. & Houlston, R.S. (2015). Genome-wide homozygosity signature and risk of Hodgkin lymphoma. Sci rep, Vol.5, p. 14315. show abstract
Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing Hodgkin lymphoma (HL) we analysed 589 HL cases and 5,199 controls genotyped for 484,072 tag single nucleotide polymorphisms (SNPs). Across the genome the cumulative distribution of ROH was not significantly different between cases and controls. Seven ROH at 4q22.3, 4q32.2, 7p12.3-14.1, 7p22.2, 10p11.22-23, 19q13.12-2 and 19p13.2 were associated with HL risk at P < 0.01. Intriguingly 4q22.3 harbours an ROH to which the nuclear factor NF-kappa-B p105 subunit (NFKB1) maps (P = 0.002). The ROH at 19q13.12-2 has previously been implicated in B-cell precursor acute lymphoblastic leukaemia. Aside from these observations which require validation, it is unlikely that levels of measured homozygosity caused by autozygosity, uniparental isodisomy or hemizygosity play a major role in defining HL risk in predominantly outbred populations..
Litchfield, K., Summersgill, B., Yost, S., Sultana, R., Labreche, K., Dudakia, D., Renwick, A., Seal, S., Al-Saadi, R., Broderick, P., et al. (2015). Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Nat commun, Vol.6, p. 5973. show abstract
Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole-exome sequencing (WES) of 42 TGCTs to comprehensively study the cancer's mutational profile. The mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per Mb) as compared with common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT, we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4 Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT..
Mitchell, J.S., Johnson, D.C., Litchfield, K., Broderick, P., Weinhold, N., Davies, F.E., Gregory, W.A., Jackson, G.H., Kaiser, M., Morgan, G.J., et al. (2015). Implementation of genome-wide complex trait analysis to quantify the heritability in multiple myeloma. Sci rep, Vol.5, p. 12473. show abstract
A sizeable fraction of multiple myeloma (MM) is expected to be explained by heritable factors. Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing MM risk. While these SNPs only explain a small proportion of the genetic risk it is unclear how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we applied Genome-Wide Complex Trait Analysis (GCTA) to 2,282 cases and 5,197 controls individuals to estimate the heritability of MM. We estimated that the heritability explained by known common MM risk SNPs identified in GWAS was 2.9% (± 2.4%), whereas the heritability explained by all common SNPs was 15.2% (± 2.8%). Comparing the heritability explained by the common variants with that from family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In summary, our results suggest that known MM SNPs only explain a small proportion of the heritability and more common SNPs remain to be identified..
Litchfield, K., Holroyd, A., Lloyd, A., Broderick, P., Nsengimana, J., Eeles, R., Easton, D.F., Dudakia, D., Bishop, D.T., Reid, A., et al. (2015). Identification of four new susceptibility loci for testicular germ cell tumour. Nat commun, Vol.6, p. 8690. show abstract
Genome-wide association studies (GWAS) have identified multiple risk loci for testicular germ cell tumour (TGCT), revealing a polygenic model of disease susceptibility strongly influenced by common variation. To identify additional single-nucleotide polymorphisms (SNPs) associated with TGCT, we conducted a multistage GWAS with a combined data set of >25,000 individuals (6,059 cases and 19,094 controls). We identified new risk loci for TGCT at 3q23 (rs11705932, TFDP2, P=1.5 × 10(-9)), 11q14.1 (rs7107174, GAB2, P=9.7 × 10(-11)), 16p13.13 (rs4561483, GSPT1, P=1.6 × 10(-8)) and 16q24.2 (rs55637647, ZFPM1, P=3.4 × 10(-9)). We additionally present detailed functional analysis of these loci, identifying a statistically significant relationship between rs4561483 risk genotype and increased GSPT1 expression in TGCT patient samples. These findings provide additional support for a polygenic model of TGCT risk and further insight into the biological basis of disease development. .
Li, W., Dobbins, S., Tomlinson, I., Houlston, R., Pal, D.K. & Strug, L.J. (2015). Prioritizing rare variants with conditional likelihood ratios. Hum hered, Vol.79 (1), pp. 5-13. show abstract
BACKGROUND: Prioritizing individual rare variants within associated genes or regions often consists of an ad hoc combination of statistical and biological considerations. From the statistical perspective, rare variants are often ranked using Fisher's exact p values, which can lead to different rankings of the same set of variants depending on whether 1- or 2-sided p values are used. RESULTS: We propose a likelihood ratio-based measure, maxLRc, for the statistical component of ranking rare variants under a case-control study design that avoids the hypothesis-testing paradigm. We prove analytically that the maxLRc is always well-defined, even when the data has zero cell counts in the 2×2 disease-variant table. Via simulation, we show that the maxLRc outperforms Fisher's exact p values in most practical scenarios considered. Using next-generation sequence data from 27 rolandic epilepsy cases and 200 controls in a region previously shown to be linked to and associated with rolandic epilepsy, we demonstrate that rankings assigned by the maxLRc and exact p values can differ substantially. CONCLUSION: The maxLRc provides reliable statistical prioritization of rare variants using only the observed data, avoiding the need to specify parameters associated with hypothesis testing that can result in ranking discrepancies across p value procedures; and it is applicable to common variant prioritization..
Henrion, M.Y., Purdue, M.P., Scelo, G., Broderick, P., Frampton, M., Ritchie, A., Meade, A., Li, P., McKay, J., Johansson, M., et al. (2015). Common variation at 1q24 1 (ALDH9A1) is a potential risk factor for renal cancer. Plos one, Vol.10 (3), p. e0122589. show abstract
So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation. .
Morris, E.J., Penegar, S., Whiffin, N., Broderick, P., Bishop, D.T., Northwood, E., Quirke, P., Finan, P. & Houlston, R.S. (2015). A retrospective observational study of the relationship between single nucleotide polymorphisms associated with the risk of developing colorectal cancer and survival. Plos one, Vol.10 (2), p. e0117816. show abstract
BACKGROUND: There is variability in clinical outcome for patients with apparently the same stage colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) mapping to chromosomes 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and Xp22 have robustly been shown to be associated with the risk of developing CRC. Since germline variation can also influence patient outcome the relationship between these SNPs and patient survivorship from CRC was examined. METHODS: All enrolled into the National Study of Colorectal Cancer Genetics (NSCCG) were genotyped for 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and xp22 SNPs. Linking this information to the National Cancer Data Repository allowed patient genotype to be related to survival. RESULTS: The linked dataset consisted of 4,327 individuals. 14q22.22 genotype defined by the SNP rs4444235 showed a significant association with overall survival. Specifically, the C allele was associated with poorer observed survival (per allele hazard ratio 1.13, 95% confidence interval 1.05-1.22, P = 0.0015). CONCLUSION: The CRC susceptibility SNP rs4444235 also appears to exert an influence in modulating patient survival and warrants further evaluation as a potential prognostic marker..
Derkach, A., Chiang, T., Gong, J., Addis, L., Dobbins, S., Tomlinson, I., Houlston, R., Pal, D.K. & Strug, L.J. (2014). Association analysis using next-generation sequence data from publicly available control groups: the robust variance score statistic. Bioinformatics, Vol.30 (15), pp. 2179-2188. show abstract
MOTIVATION: Sufficiently powered case-control studies with next-generation sequence (NGS) data remain prohibitively expensive for many investigators. If feasible, a more efficient strategy would be to include publicly available sequenced controls. However, these studies can be confounded by differences in sequencing platform; alignment, single nucleotide polymorphism and variant calling algorithms; read depth; and selection thresholds. Assuming one can match cases and controls on the basis of ethnicity and other potential confounding factors, and one has access to the aligned reads in both groups, we investigate the effect of systematic differences in read depth and selection threshold when comparing allele frequencies between cases and controls. We propose a novel likelihood-based method, the robust variance score (RVS), that substitutes genotype calls by their expected values given observed sequence data. RESULTS: We show theoretically that the RVS eliminates read depth bias in the estimation of minor allele frequency. We also demonstrate that, using simulated and real NGS data, the RVS method controls Type I error and has comparable power to the 'gold standard' analysis with the true underlying genotypes for both common and rare variants. AVAILABILITY AND IMPLEMENTATION: An RVS R script and instructions can be found at strug.research.sickkids.ca, and at https://github.com/strug-lab/RVS. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online..
Whiffin, N., Hosking, F.J., Farrington, S.M., Palles, C., Dobbins, S.E., Zgaga, L., Lloyd, A., Kinnersley, B., Gorman, M., Tenesa, A., et al. (2014). Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. Hum mol genet, Vol.23 (17), pp. 4729-4737. show abstract
To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10(-11)]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10(-10)) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10(-8)). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. .
Speedy, H.E., Di Bernardo, M.C., Sava, G.P., Dyer, M.J., Holroyd, A., Wang, Y., Sunter, N.J., Mansouri, L., Juliusson, G., Smedby, K.E., et al. (2014). A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia. Nat genet, Vol.46 (1), pp. 56-60. show abstract
Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 × 10(-9)), 4q26 (rs6858698, P = 3.07 × 10(-9)), 6q25.2 (IPCEF1, rs2236256, P = 1.50 × 10(-10)) and 7q31.33 (POT1, rs17246404, P = 3.40 × 10(-8)). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 × 10(-7)) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 × 10(-10)) and 8q22.3 (rs2511714, P = 2.90 × 10(-9)). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL. .
Sava, G.P., Speedy, H.E. & Houlston, R.S. (2014). Candidate gene association studies and risk of chronic lymphocytic leukemia: a systematic review and meta-analysis. Leuk lymphoma, Vol.55 (1), pp. 160-167. show abstract
To evaluate the contribution of association studies of candidate polymorphisms to inherited predisposition to chronic lymphocytic leukemia (CLL), we conducted a systematic review and meta-analysis of published case-control studies. We identified 36 studies which reported on polymorphic variation in 19 genes and CLL risk. Out of the 23 polymorphic variants, significant associations (p < 0.05) were seen in pooled analyses for only four variants: MDR1, rs1045642; LTA, rs2239704; CD38, rs6449182; and IFNGR1, rs4896243. These findings should be interpreted cautiously, as the estimated false positive report probabilities (FPRPs) for each association were not noteworthy (i.e. FPRP > 0.2). While studies of candidate polymorphisms may be an attractive means of identifying risk factors for CLL, the limited power of published studies to demonstrate statistically significant associations makes it essential that future analyses be based on sample sizes well-powered to identify variants having modest effects on CLL risk..
Morgan, G.J., Johnson, D.C., Weinhold, N., Goldschmidt, H., Landgren, O., Lynch, H.T., Hemminki, K. & Houlston, R.S. (2014). Inherited genetic susceptibility to multiple myeloma. Leukemia, Vol.28 (3), pp. 518-524. show abstract
Although the familial clustering of multiple myeloma (MM) supports the role of inherited susceptibility, only recently has direct evidence for genetic predisposition been demonstrated. A meta-analysis of two genome-wide association (GWA) studies has identified single-nucleotide polymorphisms (SNPs) localising to a number of genomic regions that are robustly associated with MM risk. In this review, we provide an overview of the evidence supporting a genetic contribution to the predisposition to MM and MGUS (monoclonal gammopathy of unknown significance), and the insight this gives into the biological basis of disease aetiology. We also highlight the promise of future approaches to identify further specific risk factors and their potential clinical utility. .
Park, S.L., Fesinmeyer, M.D., Timofeeva, M., Caberto, C.P., Kocarnik, J.M., Han, Y., Love, S.-., Young, A., Dumitrescu, L., Lin, Y., et al. (2014). Pleiotropic Associations of Risk Variants Identified for Other Cancers With Lung Cancer Risk: The PAGE and TRICL Consortia. Jnci-journal of the national cancer institute, Vol.106 (4).
Sawyer, E., Roylance, R., Petridis, C., Brook, M.N., Nowinski, S., Papouli, E., Fletcher, O., Pinder, S., Hanby, A., Kohut, K., et al. (2014). Genetic predisposition to in situ and invasive lobular carcinoma of the breast. Plos genet, Vol.10 (4), p. e1004285. show abstract
Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes..
Ongen, H., Andersen, C.L., Bramsen, J.B., Oster, B., Rasmussen, M.H., Ferreira, P.G., Sandoval, J., Vidal, E., Whiffin, N., Planchon, A., et al. (2014). Putative cis-regulatory drivers in colorectal cancer. Nature, Vol.512 (7512), pp. 87-90. show abstract
The cis-regulatory effects responsible for cancer development have not been as extensively studied as the perturbations of the protein coding genome in tumorigenesis. To better characterize colorectal cancer (CRC) development we conducted an RNA-sequencing experiment of 103 matched tumour and normal colon mucosa samples from Danish CRC patients, 90 of which were germline-genotyped. By investigating allele-specific expression (ASE) we show that the germline genotypes remain important determinants of allelic gene expression in tumours. Using the changes in ASE in matched pairs of samples we discover 71 genes with excess of somatic cis-regulatory effects in CRC, suggesting a cancer driver role. We correlate genotypes and gene expression to identify expression quantitative trait loci (eQTLs) and find 1,693 and 948 eQTLs in normal samples and tumours, respectively. We estimate that 36% of the tumour eQTLs are exclusive to CRC and show that this specificity is partially driven by increased expression of specific transcription factors and changes in methylation patterns. We show that tumour-specific eQTLs are more enriched for low CRC genome-wide association study (GWAS) P values than shared eQTLs, which suggests that some of the GWAS variants are tumour specific regulatory variants. Importantly, tumour-specific eQTL genes also accumulate more somatic mutations when compared to the shared eQTL genes, raising the possibility that they constitute germline-derived cancer regulatory drivers. Collectively the integration of genome and the transcriptome reveals a substantial number of putative somatic and germline cis-regulatory cancer changes that may have a role in tumorigenesis. .
Wang, Y., McKay, J.D., Rafnar, T., Wang, Z., Timofeeva, M.N., Broderick, P., Zong, X., Laplana, M., Wei, Y., Han, Y., et al. (2014). Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nat genet, Vol.46 (7), pp. 736-741. show abstract
We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data. .
Andersson, U., Wibom, C., Cederquist, K., Aradottir, S., Borg, A., Armstrong, G.N., Shete, S., Lau, C.C., Bainbridge, M.N., Claus, E.B., et al. (2014). Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer. Neuro oncol, Vol.16 (10), pp. 1333-1340. show abstract
BACKGROUND: Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. METHODS: Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer.The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. RESULTS: We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. CONCLUSIONS: Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes..
Wang, Y., McKay, J.D., Rafnar, T., Wang, Z., Timofeeva, M.N., Broderick, P., Zong, X., Laplana, M., Wei, Y., Han, Y., et al. (2014). Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer (Reprinted from Nature Genetics vol 46, pg 736, 2014 10 1038/ng 3002). Nature, Vol.513 (7517), pp. 736-+.
Labussière, M., Di Stefano, A.L., Gleize, V., Boisselier, B., Giry, M., Mangesius, S., Bruno, A., Paterra, R., Marie, Y., Rahimian, A., et al. (2014). TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations. Br j cancer, Vol.111 (10), pp. 2024-2032. show abstract
BACKGROUND: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter. METHODS: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype. RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation. CONCLUSIONS: In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors..
Jaeger, R., Harutyunyan, A.S., Rumi, E., Pietra, D., Berg, T., Olcaydu, D., Houlston, R.S., Cazzola, M. & Kralovics, R. (2014). Common germline variation at the TERT locus contributes to familial clustering of myeloproliferative neoplasms. American journal of hematology, Vol.89 (12), pp. 1107-1110.
Hemminki, K. & Houlston, R.S. (2014). Special section editorial. International journal of cancer, Vol.135 (8), pp. 1755-1755.
Weinhold, N., Johnson, D.C., Rawstron, A.C., Foersti, A., Doughty, C., Vijayakrishnan, J., Broderick, P., Dahir, N.B., Begum, D.B., Hosking, F.J., et al. (2014). Inherited genetic susceptibility to monoclonal gammopathy of unknown significance. Blood, Vol.123 (16), pp. 2513-2517.
Lucassen, A. & Houlston, R.S. (2014). The challenges of genome analysis in the health care setting. Genes (basel), Vol.5 (3), pp. 576-585. show abstract
Genome sequencing is now a sufficiently mature and affordable technology for clinical use. Its application promises not only to transform clinicians' diagnostic and predictive ability, but also to improve preventative therapies, surveillance regimes, and tailor patient treatment to an individual's genetic make-up. However, as with any technological advance, there are associated fresh challenges. While some of the ethical, legal and social aspects resulting from the generation of data from genome sequencing are generic, several nuances are unique. Since the UK government recently announced plans to sequence the genomes of 100,000 Health Service patients, and similar initiatives are being considered elsewhere, a discussion of these nuances is timely and needs to go hand in hand with formulation of guidelines and public engagement activities around implementation of sequencing in clinical practice. .
Whiffin, N. & Houlston, R.S. (2014). Architecture of inherited susceptibility to colorectal cancer: a voyage of discovery. Genes (basel), Vol.5 (2), pp. 270-284. show abstract
This review looks back at five decades of research into genetic susceptibility to colorectal cancer (CRC) and the insights these studies have provided. Initial evidence of a genetic basis of CRC stems from epidemiological studies in the 1950s and is further provided by the existence of multiple dominant predisposition syndromes. Genetic linkage and positional cloning studies identified the first high-penetrance genes for CRC in the 1980s and 1990s. More recent genome-wide association studies have identified common low-penetrance susceptibility loci and provide support for a polygenic model of disease susceptibility. These observations suggest a high proportion of CRC may arise in a group of susceptible individuals as a consequence of the combined effects of common low-penetrance risk alleles and rare variants conferring moderate CRC risks. Despite these advances, however, currently identified loci explain only a small fraction of the estimated heritability to CRC. It is hoped that a new generation of sequencing projects will help explain this missing heritability. .
Scales, M., Jäger, R., Migliorini, G., Houlston, R.S. & Henrion, M.Y. (2014). visPIG--a web tool for producing multi-region, multi-track, multi-scale plots of genetic data. Plos one, Vol.9 (9), p. e107497. show abstract
We present VISual Plotting Interface for Genetics (visPIG; http://vispig.icr.ac.uk), a web application to produce multi-track, multi-scale, multi-region plots of genetic data. visPIG has been designed to allow users not well versed with mathematical software packages and/or programming languages such as R, Matlab®, Python, etc., to integrate data from multiple sources for interpretation and to easily create publication-ready figures. While web tools such as the UCSC Genome Browser or the WashU Epigenome Browser allow custom data uploads, such tools are primarily designed for data exploration. This is also true for the desktop-run Integrative Genomics Viewer (IGV). Other locally run data visualisation software such as Circos require significant computer skills of the user. The visPIG web application is a menu-based interface that allows users to upload custom data tracks and set track-specific parameters. Figures can be downloaded as PDF or PNG files. For sensitive data, the underlying R code can also be downloaded and run locally. visPIG is multi-track: it can display many different data types (e.g association, functional annotation, intensity, interaction, heat map data,…). It also allows annotation of genes and other custom features in the plotted region(s). Data tracks can be plotted individually or on a single figure. visPIG is multi-region: it supports plotting multiple regions, be they kilo- or megabases apart or even on different chromosomes. Finally, visPIG is multi-scale: a sub-region of particular interest can be 'zoomed' in. We describe the various features of visPIG and illustrate its utility with examples. visPIG is freely available through http://vispig.icr.ac.uk under a GNU General Public License (GPLv3)..
Kinnersley, B., Buch, S., Castellví-Bel, S., Farrington, S.M., Forsti, A., Hampe, J., Hemminki, K., Hofstra, R.M., Northwood, E., Palles, C., et al. (2014). Re: Role of the Oxidative DNA Damage Repair Gene OGG1 in Colorectal Tumorigenesis. Journal of the national cancer institute, .
Wang, J., Carvajal-Carmona, L.G., Chu, J.-., Zauber, A.G., APC Trial Collaborators, , Kubo, M., Matsuda, K., Dunlop, M., Houlston, R.S., Sieber, O., et al. (2013). Germline variants and advanced colorectal adenomas: adenoma prevention with celecoxib trial genome-wide association study. Clin cancer res, Vol.19 (23), pp. 6430-6437. show abstract
PURPOSE: Identification of single-nucleotide polymorphisms (SNP) associated with development of advanced colorectal adenomas. EXPERIMENTAL DESIGN: Discovery phase: 1,406 Caucasian patients (139 advanced adenoma cases and 1,267 controls) from the Adenoma Prevention with Celecoxib (APC) trial were included in a genome-wide association study (GWAS) to identify variants associated with postpolypectomy disease recurrence. Genome-wide significance was defined as false discovery rate less than 0.05, unadjusted P = 7.4 × 10(-7). Validation phase: results were further evaluated using 4,175 familial colorectal adenoma cases and 5,036 controls from patients of European ancestry [COloRectal Gene Identification consortium (CORGI), Scotland, Australia, and VQ58]. RESULTS: Our study identified eight SNPs associated with advanced-adenoma risk in the APC trial (rs2837156, rs7278863, rs2837237, rs2837241, rs2837254, rs741864 at 21q22.2, and rs1381392 and rs17651822 at 3p24.1, at P < 10(-7) level with OR > 2). Five variants in strong pairwise linkage disequilibrium (rs7278863, rs2837237, rs741864, rs741864, and rs2837241; r(2) = 0.8-1) are in or near the coding region for the tight junction adhesion protein, IGSF5. An additional variant associated with advanced adenomas, rs1535989 [minor allele frequency, 0.11; OR, 2.09; 95% confidence interval (CI), 1.50-2.91], also predicted colorectal cancer development in a validation analysis (P = 0.019) using a series of adenoma cases or colorectal cancer (CORGI study) and 3 sets of colorectal cancer cases and controls (Scotland, VQ58, and Australia; N = 9,211). CONCLUSIONS: Our results suggest that common polymorphisms contribute to the risk of developing advanced adenomas and might also contribute to the risk of developing colorectal cancer. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance..
Enciso-Mora, V., Hosking, F.J., Kinnersley, B., Wang, Y., Shete, S., Zelenika, D., Broderick, P., Idbaih, A., Delattre, J.-., Hoang-Xuan, K., et al. (2013). Deciphering the 8q24 21 association for glioma. Hum mol genet, Vol.22 (11), pp. 2293-2302. show abstract
We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development..
Di Bernardo, M.C., Broderick, P., Harris, S., Dyer, M.J., Matutes, E., Dearden, C., Catovsky, D. & Houlston, R.S. (2013). Risk of developing chronic lymphocytic leukemia is influenced by HLA-A class I variation. Leukemia, Vol.27 (1), pp. 255-258.
Palles, C., Cazier, J.-., Howarth, K.M., Domingo, E., Jones, A.M., Broderick, P., Kemp, Z., Spain, S.L., Almeida, E.G., Salguero, I., et al. (2013). Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature genetics, Vol.45 (2), pp. 136-144.
Di Bernardo, M.C., Broderick, P., Catovsky, D. & Houlston, R.S. (2013). Common genetic variation contributes significantly to the risk of developing chronic lymphocytic leukemia. Haematologica, Vol.98 (3), pp. e23-e24.
Sadetzki, S., Bruchim, R., Oberman, B., Armstrong, G.N., Lau, C.C., Claus, E.B., Barnholtz-Sloan, J.S., Il'yasova, D., Schildkraut, J., Johansen, C., et al. (2013). Description of selected characteristics of familial glioma patients - Results from the Gliogene Consortium. European journal of cancer, Vol.49 (6), pp. 1335-1345.
Di Stefano, A.L., Enciso-Mora, V., Marie, Y., Desestret, V., Labussire, M., Boisselier, B., Mokhtari, K., Idbaih, A., Hoang-Xuan, K., Delattre, J.-., et al. (2013). Association between glioma susceptibility loci and tumour pathology defines specific molecular etiologies. Neuro-oncology, Vol.15 (5), pp. 542-547.
Palles, C., Cazier, J.-., Howarth, K.M., Domingo, E., Jones, A.M., Broderick, P., Kemp, Z., Spain, S.L., Almeida, E.G., Salguero, I., et al. (2013). Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas (vol 45, pg 136, 2013). Nature genetics, Vol.45 (6), pp. 713-713.
Dunlop, M.G., Tenesa, A., Farrington, S.M., Ballereau, S., Brewster, D.H., Koessler, T., Pharoah, P., Schafmayer, C., Hampe, J., Voelzke, H., et al. (2013). Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42 103 individuals. Gut, Vol.62 (6), pp. 871-881.
Migliorini, G., Fiege, B., Hosking, F.J., Ma, Y., Kumar, R., Sherborne, A.L., da Silva Filho, M.I., Vijayakrishnan, J., Koehler, R., Thomsen, H., et al. (2013). Variation at 10p12 2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood, Vol.122 (19), pp. 3298-3307. show abstract
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 × 10(-9)) and 10p14 marked by rs3824662 (OR = 1.31; P = 8.62 × 10(-12)). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P < .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development. .
Sava, G.P., Speedy, H.E., Di Bernardo, M.C., Deaglio, S., Karabon, L., Frydecka, I., Woszczyk, D., Rossi, D., Gaidano, G., Mansouri, L., et al. (2013). rs2072135, a low-penetrance variant for chronic lymphocytic leukaemia?. Br j haematol, Vol.162 (2), pp. 221-228. show abstract
Recent multi-stage genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are robustly associated with chronic lymphocytic leukaemia (CLL) risk. Given that most of these SNPs map to non-coding regions of the genome, it suggests that the functional basis of many GWAS signals will be through differential gene expression. By referencing publically accessible expression quantitative trait loci (eQTL) data on lymphoblastoid cells lines (LCLs) we have globally demonstrated an association between GWAS P-values and eQTLs, consistent with much of the variation in CLL risk being defined by variants impacting on gene expression. To explore using eQTL data to select GWAS SNPs for replication, we genotyped rs2072135 (GWAS P-value = 0·0024, eQTL P-value = 1·510(-19)) in five independent case-control series totalling 1968 cases and 3538 controls. While not attaining statistical significance (combined P-value = 1 × 10(-4)), rs2072135 defines a promising risk locus for CLL. Incorporating eQTL information offers an attractive strategy for selecting SNPs from GWAS for validation..
Chubb, D., Weinhold, N., Broderick, P., Chen, B., Johnson, D.C., Försti, A., Vijayakrishnan, J., Migliorini, G., Dobbins, S.E., Holroyd, A., et al. (2013). Common variation at 3q26 2, 6p21 33, 17p11 2 and 22q13 1 influences multiple myeloma risk. Nat genet, Vol.45 (10), pp. 1221-1225. show abstract
To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10(-14)), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 × 10(-11)), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 × 10(-9)) and 22q13.1 (rs877529, CBX7, P = 7.63 × 10(-16)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition. .
Köhler, A., Chen, B., Gemignani, F., Elisei, R., Romei, C., Figlioli, G., Cipollini, M., Cristaudo, A., Bambi, F., Hoffmann, P., et al. (2013). Genome-wide association study on differentiated thyroid cancer. J clin endocrinol metab, Vol.98 (10), pp. E1674-E1681. show abstract
CONTEXT: Genome-wide association studies (GWASs) of differentiated thyroid cancer (DTC) have identified associations with polymorphisms at 2q35 (DIRC3), 8p12 (NRG1), 9q22.33 (FOXE1), and 14q13.2 (NKX2-1). However, most of the inherited genetic risk factors of DTC remain to be discovered. OBJECTIVE: Our objective was to identify additional common DTC susceptibility loci. DESIGN: We conducted a GWAS in a high-incidence Italian population of 690 cases and 497 controls and followed up the most significant polymorphisms in 2 additional Italian series and in 3 low-incidence populations totaling 2958 cases and 3727 controls. RESULTS: After excluding the most robust previously identified locus (9q22.33), the strongest association was shown by rs6759952, confirming the recently published association in DIRC3 (odds ratio [OR] = 1.21, P = 6.4 × 10(-10), GWAS and all replications combined). Additionally, in the combined analysis of the Italian series, suggestive associations were attained with rs10238549 and rs7800391 in IMMP2L (OR = 1.27, P = 4.1 × 10(-6); and OR = 1.25, P = 5.7 × 10(-6)), rs7617304 in RARRES1 (OR = 1.25, P = 4.6 × 10(-5)) and rs10781500 in SNAPC4/CARD9 (OR = 1.23, P = 3.5 × 10(-5)). CONCLUSIONS: Our findings provide additional insights into the genetic and biological basis of inherited genetic susceptibility to DTC. Additional studies are needed to determine the role of the identified polymorphisms in the development of DTC and their possible use in the clinical practice..
Dobbins, S.E., Sherborne, A.L., Ma, Y.P., Bardini, M., Biondi, A., Cazzaniga, G., Lloyd, A., Chubb, D., Greaves, M.F. & Houlston, R.S., et al. (2013). The silent mutational landscape of infant MLL-AF4 pro-B acute lymphoblastic leukemia. Genes chromosomes cancer, Vol.52 (10), pp. 954-960. show abstract
Over 90% of infants (< 1-year-old) diagnosed with leukemia have pro-B acute lymphoblastic leukemia (ALL) containing the MLL-AF4 fusion. When compared with other forms of paediatric ALL affecting later B-cell differentiation, MLL-AF4 pro-B is associated with a dismal prognosis with a typical 5-year disease-free survival of <20%. MLL-AF4 may be sufficient on its own for leukemogenesis or the gene-fusion product may alternatively predispose transformed cells to global genetic instability, enhancing the acquisition of additional key mutations. To gain insight into the genomic landscape of infant MLL-AF4 pro-B ALL we performed whole genome sequencing of diagnostic leukemic blasts and matched germline samples from three MLL-AF4 pro-B ALL infants. Our analysis revealed few somatic changes (copy number abnormalities, loss of heterozygosity, or single nucleotide variants), demonstrating that only a very small number of mutations are necessary to generate infant MLL-leukemia..
Henrion, M., Frampton, M., Scelo, G., Purdue, M., Ye, Y., Broderick, P., Ritchie, A., Kaplan, R., Meade, A., McKay, J., et al. (2013). Common variation at 2q22 3 (ZEB2) influences the risk of renal cancer (vol 22, pg 825, 2012). Human molecular genetics, Vol.22 (10), pp. 2128-2128.
Whiffin, N., Dobbins, S.E., Hosking, F.J., Palles, C., Tenesa, A., Wang, Y., Farrington, S.M., Jones, A.M., Broderick, P., Campbell, H., et al. (2013). Deciphering the genetic architecture of low-penetrance susceptibility to colorectal cancer. Hum mol genet, Vol.22 (24), pp. 5075-5082. show abstract
Recent genome-wide association studies (GWASs) have identified common variants at 16 autosomal regions influencing the risk of developing colorectal cancer (CRC). To decipher the genetic basis of the association signals at these loci, we performed a meta-analysis of data from five GWASs, totalling 5626 cases and 7817 controls, using imputation to recover un-typed genotypes. To enhance our ability to discover low-frequency risk variants, in addition to using 1000 Genomes Project data as a reference panel, we made use of high-coverage sequencing data on 253 individuals, 199 with early-onset familial CRC. For 13 of the regions, it was possible to refine the association signal identifying a smaller region of interest likely to harbour the functional variant. Our analysis did not provide evidence that any of the associations at the 16 loci being a consequence of synthetic associations rather than linkage disequilibrium with a common risk variant. .
Henrion, M., Frampton, M., Scelo, G., Purdue, M., Ye, Y., Broderick, P., Ritchie, A., Kaplan, R., Meade, A., McKay, J., et al. (2013). Common variation at 2q22 3 (ZEB2) influences the risk of renal cancer. Hum mol genet, Vol.22 (4), pp. 825-831. show abstract
Genome-wide association studies (GWASs) of renal cell cancer (RCC) have identified four susceptibility loci thus far. To identify an additional RCC common susceptibility locus, we conducted a GWAS and performed a meta-analysis with published GWASs (totalling 2215 cases and 8566 controls of European background) and followed up the most significant association signals [nine single nucleotide polymorphisms (SNPs) in eight genomic regions] in 3739 cases and 8786 controls. A combined analysis identified a novel susceptibility locus mapping to 2q22.3 marked by rs12105918 (P = 1.80 × 10(-8); odds ratio 1.29, 95% CI: 1.18-1.41). The signal localizes to intron 2 of the ZEB2 gene (zinc finger E box-binding homeobox 2). Our findings suggest that genetic variation in ZEB2 influences the risk of RCC. This finding provides further insights into the genetic and biological basis of inherited genetic susceptibility to RCC..
Morris, E.J., Penegar, S., Whitehouse, L.E., Quirke, P., Finan, P., Bishop, D.T., Wilkinson, J. & Houlston, R.S. (2013). A retrospective observational study of the relationship between family history and survival from colorectal cancer. British journal of cancer, Vol.108 (7), pp. 1502-1507.
Ruark, E., Snape, K., Humburg, P., Loveday, C., Bajrami, I., Brough, R., Rodrigues, D.N., Renwick, A., Seal, S., Ramsay, E., et al. (2013). Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature, Vol.493 (7432), pp. 406-410. show abstract
Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification..
Enciso-Mora, V., Hosking, F.J., Di Stefano, A.L., Zelenika, D., Shete, S., Broderick, P., Idbaih, A., Delattre, J.-., Hoang-Xuan, K., Marie, Y., et al. (2013). Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222. Br j cancer, Vol.108 (10), pp. 2178-2185. show abstract
BACKGROUND: Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma. METHODS: To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls. RESULTS: The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10(-24), minor allele frequency ~0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown. CONCLUSION: Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma..
Ma, Y., Dobbins, S.E., Sherborne, A.L., Chubb, D., Galbiati, M., Cazzaniga, G., Micalizzi, C., Tearle, R., Lloyd, A.L., Hain, R., et al. (2013). Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia. Proc natl acad sci u s a, Vol.110 (18), pp. 7429-7433. show abstract
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. At diagnosis, the developmental timing of mutations contributing critically to clonal diversification and selection can be buried in the leukemia's covert natural history. Concordance of ALL in monozygotic, monochorionic twins is a consequence of intraplacental spread of an initiated preleukemic clone. Studying monozygotic twins with ALL provides a unique means of uncovering the timeline of mutations contributing to clonal evolution, pre- and postnatally. We sequenced the whole genomes of leukemic cells from two twin pairs with ALL to comprehensively characterize acquired somatic mutations in ALL, elucidating the developmental timing of all genetic lesions. Shared, prenatal, coding-region single-nucleotide variants were limited to the putative initiating lesions. All other nonsynonymous single-nucleotide variants were distinct between tumors and, therefore, secondary and postnatal. These changes occurred in a background of noncoding mutational changes that were almost entirely discordant in twin pairs and likely passenger mutations acquired during leukemic cell proliferation..
Frampton, M., da Silva Filho, M.I., Broderick, P., Thomsen, H., Försti, A., Vijayakrishnan, J., Cooke, R., Enciso-Mora, V., Hoffmann, P., Nöthen, M.M., et al. (2013). Variation at 3p24 1 and 6q23 3 influences the risk of Hodgkin's lymphoma. Nat commun, Vol.4, p. 2549. show abstract
In addition to HLA, recent genome-wide association studies (GWASs) of Hodgkin's lymphoma (HL) have identified susceptibility loci for HL at 2p16.1, 8q24.21 and 10p14. In this study, we perform a GWAS meta-analysis with published GWAS (totalling 1,465 cases and 6,417 controls of European background), and follow-up the most significant association signals in 2,024 cases and 1,853 controls. A combined analysis identifies new HL susceptibility loci mapping to 3p24.1 (rs3806624; P=1.14 × 10(-12), odds ratio (OR)=1.26) and 6q23.3 (rs7745098; P=3.42 × 10(-9), OR=1.21). rs3806624 localizes 5' to the EOMES (eomesodermin) gene within a p53 response element affecting p53 binding. rs7745098 maps intergenic to HBS1L and MYB, a region previously associated with haematopoiesis. These findings provide further insight into the genetic and biological basis of inherited susceptibility to HL. .
Speedy, H.E., Sava, G. & Houlston, R.S. (2013). Inherited susceptibility to CLL. Adv exp med biol, Vol.792, pp. 293-308. show abstract
Chronic lymphocytic leukaemia (CLL) is the most common lymphoid malignancy in Western countries, accounting for around a quarter of all leukaemias. Despite a strong familial basis to CLL, with risks in first-degree relatives of CLL cases being increased around sevenfold, the inherited genetic basis of CLL is currently largely unknown. The failure of genetic studies of CLL families to provide support for a major disease-causing locus has suggested a model of susceptibility based on the co-inheritance of multiple low-risk variants, some of which will be common. Recent genome-wide association studies of CLL have vindicated this model of inherited susceptibility to CLL, identifying common variants at multiple independent loci influencing risk. Here we review the evidence for inherited genetic predisposition to CLL and what the currently identified risk loci are telling us about the biology of CLL development. .
Lubbe, S.J., Di Bernardo, M.C., Broderick, P., Chandler, I. & Houlston, R.S. (2012). Comprehensive evaluation of the impact of 14 genetic variants on colorectal cancer phenotype and risk. Am j epidemiol, Vol.175 (1), pp. 1-10. show abstract
To comprehensively evaluate the impact of recently identified colorectal cancer (CRC) variants at 1q41, 3q26.2, 8q23.3, 8q24.21, 10p14, 11q23.1, 12q13.13, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12.3, and 20q13.33 on risk and CRC phenotype, the authors analyzed 8,878 cases and 6,051 controls from the United Kingdom ascertained in 1999-2007. The impact of variants on the familial CRC risk was enumerated from age-, sex-, and calendar-specific CRC rates in the 50,924 first-degree relatives of cases. Each of the 14 susceptibility loci independently influences CRC with the risk increasing with increasing number of risk alleles carried (per allele odds ratio = 1.13; P = 2.99 × 10(-58)) and, for those within the upper quintile, there is a 2.3-fold increased risk. In first-degree relatives of cases with ≤17, 18-21, and ≥22 risk alleles, standardized incidence ratios were 1.76, 2.08, and 2.25, respectively. Although the discriminatory attributes of the 14 CRC susceptibility loci for individual risk prediction are poor (area under the curve = 0.58), they may allow subgroups of the population at different CRC risks to be distinguished..
Lubbe, S.J., Whiffin, N., Chandler, I., Broderick, P. & Houlston, R.S. (2012). Relationship between 16 susceptibility loci and colorectal cancer phenotype in 3146 patients. Carcinogenesis, Vol.33 (1), pp. 108-112. show abstract
Recent genome-wide association studies have identified single-nucleotide polymorphisms at 16 genetic loci associated with colorectal cancer risk: rs6691170 (1q41), rs10936599 (3q26.2), rs16892766 (8q23.3), rs6983267 (8q24.21), rs10795668 (10p14), rs3802842 (11q23.1), rs11169552 (12q13.13), rs4444235, rs1957636 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.11), rs961253 and rs4813802 (20p12.3) and rs4925386 (20q13.33). In the present study, we examined whether these variants are preferentially associated with tumour subtype-tumour site, stage, degree of differentiation and microsatellite instability status-in 3146 patients. Several loci showed statistically significant associations with specific phenotypes notably rs6691170 and rs3802842 associated with microsatellite stable rectal disease; rs4779584, rs961253 and rs4813802 associated with microsatellite stable colonic disease and rs4444235 and rs4925386 with microsatellite instability colonic disease. These findings are consistent with pathogenic variants in loci differentially impacting on distinct morphogenetic pathways consistent with aetiologically different risk factors in the development of colorectal cancer..
Johnson, N., Walker, K., Gibson, L.J., Orr, N., Folkerd, E., Haynes, B., Palles, C., Coupland, B., Schoemaker, M., Jones, M., et al. (2012). CYP3A variation, premenopausal estrone levels, and breast cancer risk. J natl cancer inst, Vol.104 (9), pp. 657-669. show abstract
BACKGROUND: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women. METHODS: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided. RESULTS: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82). CONCLUSIONS: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer..
Shi, J., Chatterjee, N., Rotunno, M., Wang, Y., Pesatori, A.C., Consonni, D., Li, P., Wheeler, W., Broderick, P., Henrion, M., et al. (2012). Inherited Variation at Chromosome 12p13 33, Including RAD52, Influences the Risk of Squamous Cell Lung Carcinoma. Cancer discovery, Vol.2 (2), pp. 131-139.
Tomlinson, I.P., Houlston, R.S., Montgomery, G.W., Sieber, O.M. & Dunlop, M.G. (2012). Investigation of the effects of DNA repair gene polymorphisms on the risk of colorectal cancer. Mutagenesis, Vol.27 (2), pp. 219-223.
Houlston, R.S. & members of COGENT, (2012). COGENT (COlorectal cancer GENeTics) revisited. Mutagenesis, Vol.27 (2), pp. 143-151. show abstract
Many colorectal cancers (CRCs) develop in genetically susceptible individuals most of whom are not carriers of germ line mismatch repair or APC gene mutations and much of the heritable risk of CRC appears to be attributable to the co-inheritance of multiple low-risk variants. The accumulated experience to date in identifying this class of susceptibility allele has highlighted the need to conduct statistically and methodologically rigorous studies and the need for the multi-centre collaboration. This has been the motivation for establishing the COGENT (COlorectal cancer GENeTics) consortium which now includes over 20 research groups in Europe, Australia, the Americas, China and Japan actively working on CRC genetics. Here, we review the rationale for identifying low-penetrance variants for CRC and the current and future challenges for COGENT..
Wibom, C., Sjöström, S., Henriksson, R., Brännström, T., Broholm, H., Rydén, P., Johansen, C., Collatz-Laier, H., Hepworth, S., McKinney, P.A., et al. (2012). DNA-repair gene variants are associated with glioblastoma survival. Acta oncol, Vol.51 (3), pp. 325-332. show abstract
Patient outcome from glioma may be influenced by germline variation. Considering the importance of DNA repair in cancer biology as well as in response to treatment, we studied the relationship between 1458 SNPs, which captured the majority of the common genetic variation in 136 DNA repair genes, in 138 glioblastoma samples from Sweden and Denmark. We confirmed our findings in an independent cohort of 121 glioblastoma patients from the UK. Our analysis revealed nine SNPs annotating MSH2, RAD51L1 and RECQL4 that were significantly (p < 0.05) associated with glioblastoma survival..
Kinnersley, B., Migliorini, G., Broderick, P., Whiffin, N., Dobbins, S.E., Casey, G., Hopper, J., Sieber, O., Lipton, L., Kerr, D.J., et al. (2012). The TERT variant rs2736100 is associated with colorectal cancer risk. Br j cancer, Vol.107 (6), pp. 1001-1008. show abstract
BACKGROUND: Polymorphic variation at the 5p15.33 (TERT-CLPTM1L) locus is associated with the risk of many cancers but a relationship with colorectal cancer (CRC) risk has yet to be defined. METHODS: We used data from six genome-wide association studies (GWAS) of CRC, linkage disequilibrium mapping and imputation, to examine the relationship between 73 single-nucleotide polymorphisms at 5p15.33 and CRC risk in detail. RESULTS: rs2736100, which localises to intron 2 of TERT, provided the strongest evidence of an association with CRC (P=2.28 × 10⁻⁴). The association was also shown in an independent series of 10 047 CRC cases and 6918 controls (P=0.02). A meta-analysis of all seven studies (totalling 16 039 cases, 16 430 controls) provided increased evidence of association (P=2.49 × 10⁻⁵; per allele odds ratio=1.07). The association of rs2736100 on CRC risk was shown to be independent of 15 low-penetrance variants previously identified. CONCLUSION: The rs2736100 association demonstrates an influence of variation at 5p15.33 on CRC risk and further evidence that the 5p15.33 (TERT-CLPTM1L) locus has pleiotropic effects (reflecting generic or lineage-specific effects) on cancer risk..
Morgan, G., Johnsen, H.E., Goldschmidt, H., Palumbo, A., Cavo, M., Sonneveld, P., Miguel, J.S., Chim, C.S., Browne, P., Einsele, H., et al. (2012). MyelomA Genetics International Consortium. Leuk lymphoma, Vol.53 (5), pp. 796-800. show abstract
While the etiology of multiple myeloma (MM) is largely unknown, evidence for an inherited genetic susceptibility is provided by the two-fold increased risk of the disease seen in first-degree relatives of cases of MM. It is likely that part of this heritable risk is a consequence of the co-inheritance of low-risk genetic variants. The accumulated experience to date in identifying risk variants for other tumors has highlighted difficulties in conducting statistically and methodologically rigorous studies. The MyelomA Genetics International Consortium (MAGIC) includes 16 research groups in Europe, Asia, Australasia, the Middle East and the Americas engaged in studying the genetics of MM. The first goal of MAGIC is to identify and characterize common genetic variants for MM through association-based analyses. Here, we review the rationale for identifying genetic risk variants for MM and our proposed strategy for establishing MAGIC..
Davies, J.L., Cazier, J.-., Dunlop, M.G., Houlston, R.S., Tomlinson, I.P. & Holmes, C.C. (2012). A Novel Test for Gene-Ancestry Interactions in Genome-Wide Association Data. Plos one, Vol.7 (12).
Gorlova, O., Broderick, P., Field, J., Schwartz, A., Houlston, R., Ying, J., Yu, X., Zhao, Y., Wenzlaff, A., Zhang, R., et al. (2012). GENOME-WIDE ASSOCIATION STUDY OF LUNG CANCER IN NEVER SMOKERS. Journal of thoracic oncology, Vol.7 (9), pp. S169-S169.
Liu, Y., Melin, B.S., Rajaraman, P., Wang, Z., Linet, M., Shete, S., Amos, C.I., Lau, C.C., Scheurer, M.E., Tsavachidis, S., et al. (2012). Insight in glioma susceptibility through an analysis of 6p22 3, 12p13 33-12 1, 17q22-23 2 and 18q23 SNP genotypes in familial and non-familial glioma. Human genetics, Vol.131 (9), pp. 1507-1517.
Huang, X., Kushekhar, K., Nolte, I., Kooistra, W., Visser, L., Bouwman, I., Kouprie, N., Veenstra, R., van Imhoff, G., Olver, B., et al. (2012). HLA Associations in Classical Hodgkin Lymphoma: EBV Status Matters. Plos one, Vol.7 (7).
Enciso-Mora, V., Hosking, F.J., Sheridan, E., Kinsey, S.E., Lightfoot, T., Roman, E., Irving, J.A., Tomlinson, I.P., Allan, J.M., Taylor, M., et al. (2012). Common genetic variation contributes significantly to the risk of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia, Vol.26 (10), pp. 2212-2215. show abstract
Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence that common genetic variation influences the risk of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), identifying risk single-nucleotide polymorphisms (SNPs) localizing to 7p12.2, 9p21.3, 10q21.2 and 14q11.2. The testing of SNPs individually for an association in GWA studies necessitates the imposition of a very stringent P-value to address the issue of multiple testing. While this reduces false positives, real associations may be missed and therefore any estimate of the total heritability will be negatively biased. Using GWAS data on 823 BCP-ALL cases by considering all typed SNPs simultaneously, we have calculated that 24% of the total variation in BCP-ALL risk is accounted for common genetic variation (95% confidence interval 6-42%). Our findings provide support for a polygenic basis for susceptibility to BCP-ALL and have wider implications for future searches for novel disease-causing risk variants..
Sun, X., Vengoechea, J., Elston, R., Chen, Y., Amos, C.I., Armstrong, G., Bernstein, J.L., Claus, E., Davis, F., Houlston, R.S., et al. (2012). A Variable Age of Onset Segregation Model for Linkage Analysis, with Correction for Ascertainment, Applied to Glioma. Cancer epidemiology biomarkers & prevention, Vol.21 (12), pp. 2242-2251.
Rajaraman, P., Melin, B.S., Wang, Z., McKean-Cowdin, R., Michaud, D.S., Wang, S.S., Bondy, M., Houlston, R., Jenkins, R.B., Wrensch, M., et al. (2012). Genome-wide association study of glioma and meta-analysis. Human genetics, Vol.131 (12), pp. 1877-1888.
Robertson, L., Hanson, H., Seal, S., Warren-Perry, M., Hughes, D., Howell, I., Turnbull, C., Houlston, R., Shanley, S., Butler, S., et al. (2012). BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years. Br j cancer, Vol.106 (6), pp. 1234-1238. show abstract
BACKGROUND: Triple-negative (TN) tumours are the predominant breast cancer subtype in BRCA1 mutation carriers. Recently, it was proposed that all individuals below 50 years of age with TN breast cancer should be offered BRCA testing. We have evaluated the BRCA1 mutation frequency and the implications for clinical practice of undertaking genetic testing in women with TN breast cancer. METHODS: We undertook BRCA1 mutation analysis in 308 individuals with TN breast cancer, 159 individuals from unselected series of breast cancer and 149 individuals from series ascertained on the basis of young age and/or family history. RESULTS: BRCA1 mutations were present in 45 out of 308 individuals. Individuals with TN cancer <50 years had >10% likelihood of carrying a BRCA1 mutation in both the unselected (11 out of 58, 19%) and selected (26 out of 111, 23%) series. However, over a third would not have been offered testing using existing criteria. We estimate that testing all individuals with TN breast cancer <50 years would generate an extra 1200 tests annually in England. CONCLUSION: Women with TN breast cancer diagnosed below 50 years have >10% likelihood of carrying a BRCA1 mutation and are therefore eligible for testing in most centres. However, implementation may place short-term logistical and financial burdens on genetic services..
Ross, G.M., Johnson, N., Orr, N., Walker, K., Gibson, L., Folkerd, E., Haynes, B., Palles, C., Coupland, B., Shoemaker, M., et al. (2012). Impact of CYP3A variation on estrone levels and breast cancer risk. Cancer research, Vol.72.
Timofeeva, M.N., Hung, R.J., Rafnar, T., Christiani, D.C., Field, J.K., Bickeboeller, H., Risch, A., McKay, J.D., Wang, Y., Dai, J., et al. (2012). Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls. Human molecular genetics, Vol.21 (22), pp. 4980-4995.
Spain, S.L., Carvajal-Carmona, L.G., Howarth, K.M., Jones, A.M., Su, Z., Cazier, J.-., Williams, J., Aaltonen, L.A., Pharoah, P., Kerr, D.J., et al. (2012). Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13 13. Hum mol genet, Vol.21 (4), pp. 934-946. show abstract
In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases..
Lubbe, S.J., Pittman, A.M., Olver, B., Lloyd, A., Vijayakrishnan, J., Naranjo, S., Dobbins, S., Broderick, P., Gómez-Skarmeta, J.L. & Houlston, R.S., et al. (2012). The 14q22 2 colorectal cancer variant rs4444235 shows cis-acting regulation of BMP4. Oncogene, Vol.31 (33), pp. 3777-3784. show abstract
Common genetic variation at human 14q22.2 tagged by rs4444235 is significantly associated with colorectal cancer (CRC) risk. Re-sequencing was used to comprehensively annotate the 17kb region of strong linkage disequilibrium encompassing rs4444235. Through bioinformatic analyses using H3K4Me1, H3K4Me3, and DNase-I hypersensitivity chromatin signatures and evolutionary conservation we identified seven candidate disease-causing single-nucleotide polymorphisms mapping to six regions within the 17-kb region predicted to have regulatory potential. Reporter gene studies of these regions demonstrated that the element to which rs4444235 maps acts as an allele-specific transcriptional enhancer. Allele-specific expression studies in CRC cell lines heterozygous for rs4444235 showed significantly increased expression of bone morphogenetic protein-4 (BMP4) associated with the risk allele (P<0.001). These data provide evidence for a functional basis for the non-coding risk variant rs4444235 at 14q22.2 and emphasizes the importance of genetic variation in the BMP pathway genes as determinants of CRC risk..
Hemminki, K., Houlston, R., Sundquist, J., Sundquist, K. & Shu, X. (2012). Co-Morbidity between Early-Onset Leukemia and Type 1 Diabetes - Suggestive of a Shared Viral Etiology?. Plos one, Vol.7 (6).
Slager, S.L., Skibola, C.F., Di Bernardo, M.C., Conde, L., Broderick, P., McDonnell, S.K., Goldin, L.R., Croft, N., Holroyd, A., Harris, S., et al. (2012). Common variation at 6p21 31 (BAK1) influences the risk of chronic lymphocytic leukemia. Blood, Vol.120 (4), pp. 843-846.
Ma, Y.P., van Leeuwen, F.E., Cooke, R., Broeks, A., Enciso-Mora, V., Olver, B., Lloyd, A., Broderick, P., Russell, N.S., Janus, C., et al. (2012). FGFR2 genotype and risk of radiation-associated breast cancer in Hodgkin lymphoma. Blood, Vol.119 (4), pp. 1029-1031. show abstract
Women treated at young ages with supradiaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide association studies have identified 14 independently replicated common single nucleotide polymorphisms that influence breast cancer risk. To examine whether these variants contribute to risk of radiation-associated breast cancer in HL, we analyzed 2 independent case-control series, from the United Kingdom and The Netherlands, totaling 693 HL patients, 232 with breast cancer and 461 without. rs1219648, which annotates the FGFR2 gene, was associated with risk in both series (combined per-allele odds ratio = 1.59, 95% confidence interval: 1.26-2.02; P = .000111). These data provide evidence that genetic variation in FGFR2 influences radiation-induced breast cancer risk..
Dunlop, M.G., Dobbins, S.E., Farrington, S.M., Jones, A.M., Palles, C., Whiffin, N., Tenesa, A., Spain, S., Broderick, P., Ooi, L.-., et al. (2012). Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. Nat genet, Vol.44 (7), pp. 770-776. show abstract
We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC..
Frampton, M. & Houlston, R. (2012). Generation of artificial FASTQ files to evaluate the performance of next-generation sequencing pipelines. Plos one, Vol.7 (11), p. e49110. show abstract
Pipelines for the analysis of Next-Generation Sequencing (NGS) data are generally composed of a set of different publicly available software, configured together in order to map short reads of a genome and call variants. The fidelity of pipelines is variable. We have developed ArtificialFastqGenerator, which takes a reference genome sequence as input and outputs artificial paired-end FASTQ files containing Phred quality scores. Since these artificial FASTQs are derived from the reference genome, it provides a gold-standard for read-alignment and variant-calling, thereby enabling the performance of any NGS pipeline to be evaluated. The user can customise DNA template/read length, the modelling of coverage based on GC content, whether to use real Phred base quality scores taken from existing FASTQ files, and whether to simulate sequencing errors. Detailed coverage and error summary statistics are outputted. Here we describe ArtificialFastqGenerator and illustrate its implementation in evaluating a typical bespoke NGS analysis pipeline under different experimental conditions. ArtificialFastqGenerator was released in January 2012. Source code, example files and binaries are freely available under the terms of the GNU General Public License v3.0. from https://sourceforge.net/projects/artfastqgen/..
Orr, N., Lemnrau, A., Cooke, R., Fletcher, O., Tomczyk, K., Jones, M., Johnson, N., Lord, C.J., Mitsopoulos, C., Zvelebil, M., et al. (2012). Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk. Nat genet, Vol.44, pp. 1182-1184. show abstract
We conducted a genome-wide association study of male breast cancer comprising 823 cases and 2,795 controls of European ancestry, with validation in independent sample sets totaling 438 cases and 474 controls. A SNP in RAD51B at 14q24.1 was significantly associated with male breast cancer risk (P = 3.02 x 10(-13); odds ratio (OR) = 1.57). We also refine association at 16q12.1 to a SNP within TOX3 (P = 3.87 x 10(-15); OR = 1.50)..
Lubbe, S.J., Pittman, A.M., Matijssen, C., Twiss, P., Olver, B., Lloyd, A., Qureshi, M., Brown, N., Nye, E., Stamp, G., et al. (2011). Evaluation of Germline BMP4 Mutation as a Cause of Colorectal Cancer. Hum mutat, Vol.32 (1), pp. E1928-E1938. show abstract
Transforming growth factor-beta (TGF-beta) signalling plays a key role in colorectal cancer (CRC). Bone morphogenetic protein-4 (BMP4) is a member of the TGF-beta family of signal transduction molecules. To examine if germline mutation in BMP4 causes CRC we analysed 504 genetically enriched CRC cases (by virtue of early-onset disease, family history of CRC) for mutations in the coding sequence of BMP4. We identified three pathogenic mutations, p. R286X (g.8330C>T), p.W325C (g.8449G>T) and p.C373S (g.8592G>C), amongst the CRC cases which were not observed in 524 healthy controls. p. R286X localizes to the N-terminal of the TGF-beta 1 prodomain truncating the protein prior to the active domain. p.W325C and p.C373S mutations are predicted from protein homology modelling with BMP2 to impact deleteriously on BMP4 function. Segregation of p.C373S with adenoma and hyperplastic polyp in first-degree relatives of the case suggests germline mutations may confer a juvenile polyposis-type phenotype. These findings suggest mutation of BMP4 is a cause of CRC and the value of protein-based modelling in the elucidation of rare disease-causing variants. (C) 2010 Wiley-Liss, Inc..
Transforming growth factor-β (TGF-β) signalling plays a key role in colorectal cancer (CRC). Bone morphogenetic protein-4 (BMP4) is a member of the TGF-β family of signal transduction molecules. To examine if germline mutation in BMP4 causes CRC we analysed 504 genetically enriched CRC cases (by virtue of early-onset disease, family history of CRC) for mutations in the coding sequence of BMP4. We identified three pathogenic mutations, p.R286X (g.8330C>T), p.W325C (g.8449G>T) and p.C373S (g.8592G>C), amongst the CRC cases which were not observed in 524 healthy controls. p.R286X localizes to the N-terminal of the TGF-β1 prodomain truncating the protein prior to the active domain. p.W325C and p.C373S mutations are predicted from protein homology modelling with BMP2 to impact deleteriously on BMP4 function. Segregation of p.C373S with adenoma and hyperplastic polyp in first-degree relatives of the case suggests germline mutations may confer a juvenile polyposis-type phenotype. These findings suggest mutation of BMP4is a cause of CRC and the value of protein-based modelling in the elucidation of rare disease-causing variants..
Dobbins, S.E., Hosking, F.J., Shete, S., Armstrong, G., Swerdlow, A., Liu, Y., Yu, R., Lau, C., Schoemaker, M.J., Hepworth, S.J., et al. (2011). Allergy and glioma risk: test of association by genotype. Int j cancer, Vol.128 (7), pp. 1736-1740. show abstract
Although epidemiological studies have suggested an association between atopy and glioma risk, these observations have been based on self-reporting of allergic conditions raising the possibility that associations may be noncausal and arise as a consequence of bias, reverse causation or other artifacts. Genetic information provides an alternative approach to investigate the relationship avoiding such biases. We analyzed 1,878 glioma cases and 3,670 controls for variants at 2q12, 5q12.1, 11q13 and 17q21 that are associated with asthma or eczema risk at p < 5.0 × 10(-7) . The SNP rs7216389, which tags the 3' flanking region of ORMDL3 at 17q21 and has been associated with childhood asthma, was correlated with increased glioma risk (OR = 1.10; 95% CI: 1.01-1.19). These data provide evidence for a correlation between asthma susceptibility and glioma risk and illustrate the value of using genetics as an investigative tool for developing etiological hypotheses..
Hemminki, K., Foersti, A., Houlston, R. & Bermejo, J.L. (2011). Searching for the Missing Heritability of Complex Diseases. Human mutation, Vol.32 (2), pp. 259-262.
Zhao, D.-., Chandler, I., Chen, Z.-., Pan, H.-., Popat, S., Shao, Y.-. & Houlston, R.S. (2011). Mismatch repair, minichromosome maintenance complex component 2, cyclin A, and transforming growth factor β receptor type II as prognostic factors for colorectal cancer: results of a 10-year prospective study using tissue microarray analysis. Chin med j (engl), Vol.124 (4), pp. 483-490. show abstract
BACKGROUND: The expression of genes encoding a number of pathogenetic pathways involved in colorectal cancer could potentially act as prognostic markers. Large prospective studies are required to establish their relevance to disease prognosis. METHODS: We investigated the relevance of 19 markers in 790 patients enrolled in a large randomised trial of 5-fluorouracil using immunohistochemistry and chromogenic in situ hybridisation. The relationship between overall 10-year survival and marker status was assessed. RESULTS: Minichromosome maintenance complex component 2 (MCM2) and cyclin A were significantly associated with overall survival. Elevated MCM2 expression was associated with a better prognosis (HR = 0.63, 95%CI: 0.46 - 0.86). Cyclin A expression above the median predicted an improved patient prognosis (HR = 0.71, 95%CI: 0.53 - 0.95). For mismatch repair deficiency and transforming growth factor β receptor type II (TGFBRII) overexpression there was a borderline association with a poorer prognosis (HR = 0.69, 95%CI: 0.46 - 1.04 and HR = 2.11, 95%CI: 1.02 - 4.40, respectively). No apparent associations were found for other markers. CONCLUSION: This study identified cell proliferation and cyclin A expression as prognostic indicators of patient outcome in colorectal cancer..
Fletcher, O., Johnson, N., Orr, N., Hosking, F.J., Gibson, L.J., Walker, K., Zelenika, D., Gut, I., Heath, S., Palles, C., et al. (2011). Novel breast cancer susceptibility locus at 9q31 2: results of a genome-wide association study. J natl cancer inst, Vol.103 (5), pp. 425-435. show abstract
BACKGROUND: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. METHODS: We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided. RESULTS: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6)). CONCLUSIONS: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects..
Yu, H., Zhao, H., Wang, L.-., Han, Y., Chen, W.V., Amos, C.I., Rafnar, T., Sulem, P., Stefansson, K., Landi, M.T., et al. (2011). An analysis of single nucleotide polymorphisms of 125 DNA repair genes in the Texas genome-wide association study of lung cancer with a replication for the XRCC4 SNPs. Dna repair (amst), Vol.10 (4), pp. 398-407. show abstract
DNA repair genes are important for maintaining genomic stability and limiting carcinogenesis. We analyzed all single nucleotide polymorphisms (SNPs) of 125 DNA repair genes covered by the Illumina HumanHap300 (v1.1) BeadChips in a previously conducted genome-wide association study (GWAS) of 1154 lung cancer cases and 1137 controls and replicated the top-hits of XRCC4 SNPs in an independent set of 597 cases and 611 controls in Texas populations. We found that six of 20 XRCC4 SNPs were associated with a decreased risk of lung cancer with a P-value of 0.01 or lower in the discovery dataset, of which the most significant SNP was rs10040363 (P for allelic test=4.89 x 10⁻⁴). Moreover, the data in this region allowed us to impute a potentially functional SNP rs2075685 (imputed P for allelic test=1.3 x 10⁻³). A luciferase reporter assay demonstrated that the rs2075685G>T change in the XRCC4 promoter increased expression of the gene. In the replication study of rs10040363, rs1478486, rs9293329, and rs2075685, however, only rs10040363 achieved a borderline association with a decreased risk of lung cancer in a dominant model (adjusted OR=0.80, 95% CI=0.62-1.03 and P=0.079). In the final combined analysis of both the Texas GWAS discovery and replication datasets, the strength of the association was increased for rs10040363 (adjusted OR=0.77, 95% CI=0.66-0.89, P(dominant)=5 x 10⁻⁴ and P for trend=5 x 10⁻⁴) and rs1478486 (adjusted OR=0.82, 95% CI=0.71-0.94, P(dominant)=6 x 10⁻³ and P for trend=3.5 x 10⁻³). Finally, we conducted a meta-analysis of these XRCC4 SNPs with available data from published GWA studies of lung cancer with a total of 12,312 cases and 47,921 controls, in which none of these XRCC4 SNPs was associated with lung cancer risk. It appeared that rs2075685, although associated with increased expression of a reporter gene and lung cancer risk in the Texas populations, did not have an effect on lung cancer risk in other populations. This study underscores the importance of replication using published data in larger populations..
Hosking, F.J., Leslie, S., Dilthey, A., Moutsianas, L., Wang, Y., Dobbins, S.E., Papaemmanuil, E., Sheridan, E., Kinsey, S.E., Lightfoot, T., et al. (2011). MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia. Blood, Vol.117 (5), pp. 1633-1640. show abstract
A role for specific human leukocyte antigen (HLA) variants in the etiology of childhood acute lymphoblastic leukemia (ALL) has been extensively studied over the last 30 years, but no unambiguous association has been identified. To comprehensively study the relationship between genetic variation within the 4.5 Mb major histocompatibility complex genomic region and precursor B-cell (BCP) ALL risk, we analyzed 1075 observed and 8176 imputed single nucleotide polymorphisms and their related haplotypes in 824 BCP-ALL cases and 4737 controls. Using these genotypes we also imputed both common and rare alleles at class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1, HLA-DQA1, and HLA-DQB1) HLA loci. Overall, we found no statistically significant association between variants and BCP-ALL risk. We conclude that major histocompatibility complex-defined variation in immune-mediated response is unlikely to be a major risk factor for BCP-ALL..
Slade, I., Bacchelli, C., Davies, H., Murray, A., Abbaszadeh, F., Hanks, S., Barfoot, R., Burke, A., Chisholm, J., Hewitt, M., et al. (2011). DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J med genet, Vol.48 (4), pp. 273-278. show abstract
BACKGROUND: Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB). AIM: To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer. METHODS AND RESULTS: The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional DICER1 mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli-Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli-Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. DICER1 mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli-Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from DICER1 mutation-positive patients showed universal retention of the wild-type allele. DICER1 truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations. CONCLUSION: Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli-Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which DICER1 mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition 'DICER1 syndrome'. ACCESSION NUMBERS: The cDNA Genbank accession number for the DICER1 sequence reported in this paper is NM_030621.2..
Wei, S., Niu, J., Zhao, H., Liu, Z., Wang, L.-., Han, Y., Chen, W.V., Amos, C.I., Rafnar, T., Sulem, P., et al. (2011). Association of a novel functional promoter variant (rs2075533 C>T) in the apoptosis gene TNFSF8 with risk of lung cancer--a finding from Texas lung cancer genome-wide association study. Carcinogenesis, Vol.32 (4), pp. 507-515. show abstract
Published genome-wide association studies (GWASs) have identified few variants in the known biological pathways involved in lung cancer etiology. To mine the possibly hidden causal single nucleotide polymorphisms (SNPs), we explored all SNPs in the extrinsic apoptosis pathway from our published GWAS dataset for 1154 lung cancer cases and 1137 cancer-free controls. In an initial association analysis of 611 tagSNPs in 41 apoptosis-related genes, we identified only 10 tagSNPs associated with lung cancer risk with a P value<10(-2), including four tagSNPs in DAPK1 and three tagSNPs in TNFSF8. Unlike DAPK1 SNPs, TNFSF8 rs2181033 tagged other four predicted functional but untyped SNPs (rs776576, rs776577, rs31813148 and rs2075533) in the promoter region. Therefore, we further tested binding affinity of these four SNPs by performing the electrophoretic mobility shift assay. We found that only rs2075533T allele modified levels of nuclear proteins bound to DNA, leading to significantly decreased expression of luciferase reporter constructs by 5- to -10-fold in H1299, HeLa and HCT116 cell lines compared with the C allele. We also performed a replication study of the untyped rs2075533 in an independent Texas population but did not confirm the protective effect. We further performed a mini meta-analysis for SNPs of TNFSF8 obtained from other four published lung cancer GWASs with 12 214 cases and 47 721 controls, and we found that only rs3181366 (r2=0.69 with the untyped rs2075533) was associated to lung cancer risk (P=0.008). Our findings suggest a possible role of novel TNFSF8 variants in susceptibility to lung cancer..
Rio Frio, T., Bahubeshi, A., Kanellopoulou, C., Hamel, N., Niedziela, M., Sabbaghian, N., Pouchet, C., Gilbert, L., O'Brien, P.K., Serfas, K., et al. (2011). DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. Jama, Vol.305 (1), pp. 68-77. show abstract
CONTEXT: Nontoxic multinodular goiter (MNG) is frequently observed in the general population, but little is known about the underlying genetic susceptibility to this disease. Familial cases of MNG have been reported, and published reports describe 5 families that also contain at least 1 individual with a Sertoli-Leydig cell tumor of the ovary (SLCT). Germline mutations in DICER1, a gene that codes for an RNase III endoribonuclease, have been identified in families affected by pleuropulmonary blastoma (PPB), some of whom include cases of MNG and gonadal tumors such as SLCTs. OBJECTIVE: To determine whether familial MNG with or without SLCT in the absence of PPB was associated with mutations in DICER1. DESIGN, SETTING, AND PATIENTS: From September 2009 to September 2010, we screened 53 individuals from 2 MNG and 3 MNG/SLCT families at McGill University for mutations in DICER1. We investigated blood lymphocytes and MNG and SLCT tissue from family members for loss of the wild-type DICER1 allele (loss of heterozygosity), DICER1 expression, and microRNA (miRNA) dysregulation. MAIN OUTCOME MEASURE: Detection of germline DICER1 gene mutations in familial MNG with and without SLCT. RESULTS: We identified and characterized germline DICER1 mutations in 37 individuals from 5 families. Two mutations were predicted to be protein truncating, 2 resulted in in-frame deletions, and 1 was a missense mutation. Molecular analysis of the 3 SLCTs showed no loss of heterozygosity of DICER1, and immunohistochemical analysis in 2 samples showed strong expression of DICER1 in Sertoli cells but weak staining of Leydig cells. miRNA profiling of RNA from lymphoblastoid cell lines from both affected and unaffected members of the familial MNG cases revealed miRNA perturbations in DICER1 mutation carriers. CONCLUSIONS: DICER1 mutations are associated with both familial MNG and MNG with SLCT, independent of PPB. These germline DICER1 mutations are associated with dysregulation of miRNA expression patterns..
Abulí, A., Fernández-Rozadilla, C., Giráldez, M.D., Muñoz, J., Gonzalo, V., Bessa, X., Bujanda, L., Reñé, J.M., Lanas, A., García, A.M., et al. (2011). A two-phase case-control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22. Br j cancer, Vol.105 (6), pp. 870-875. show abstract
BACKGROUND: Colorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22-31, 3q21-24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22-31, and EPHB1 and MRAS in 3q21-q24. METHODS: CRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single-nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22-31 and 3q21-q24. RESULTS: None of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk. CONCLUSIONS: TOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts..
Tomlinson, I.P., Carvajal-Carmona, L.G., Dobbins, S.E., Tenesa, A., Jones, A.M., Howarth, K., Palles, C., Broderick, P., Jaeger, E.E., Farrington, S., et al. (2011). Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. Plos genet, Vol.7 (6), p. e1002105. show abstract
Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases..
Sherborne, A.L., Hemminki, K., Kumar, R., Bartram, C.R., Stanulla, M., Schrappe, M., Petridou, E., Semsei, A.F., Szalai, C., Sinnett, D., et al. (2011). Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia. Haematologica, Vol.96 (7), pp. 1049-1054. show abstract
Acute lymphoblastic leukemia is the major pediatric cancer in developed countries. To date most association studies of acute lymphoblastic leukemia have been based on the candidate gene approach and have evaluated a restricted number of polymorphisms. Such studies have served to highlight difficulties in conducting statistically and methodologically rigorous investigations into acute lymphoblastic leukemia risk. Recent genome-wide association studies of childhood acute lymphoblastic leukemia have provided robust evidence that common variation at four genetic loci confers a modest increase in risk. The accumulated experience to date and relative lack of success of initial efforts to identify novel acute lymphoblastic leukemia predisposition loci emphasize the need for alternative study designs and methods. The International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium includes 12 research groups in Europe, Asia, the Middle East and the Americas engaged in studying the genetics of acute lymphoblastic leukemia. The initial goal of this consortium is to identify and characterize low-penetrance susceptibility variants for acute lymphoblastic leukemia through association-based analyses. Efforts to develop genome-wide association studies of acute lymphoblastic leukemia, in terms of both sample size and single nucleotide polymorphism coverage, and to increase the number of single nucleotide polymorphisms taken forward to large-scale replication should lead to the identification of additional novel risk variants for acute lymphoblastic leukemia. Ethnic differences in the risk of acute lymphoblastic leukemia are well recognized and thus in assessing the interplay between inherited and non-genetic risk factors, analyses using different population cohorts with different incidence rates are likely to be highly informative. Given that the frequency of many acute lymphoblastic leukemia subgroups is small, identifying differential effects will realistically only be possible through multi-center pooled analyses. Here, we review the rationale for identifying genetic risk variants for acute lymphoblastic leukemia and our proposed strategy for establishing the International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium..
Wang, Y., Broderick, P., Matakidou, A., Vijayakrishnan, J., Eisen, T. & Houlston, R.S. (2011). Variation in TP63 is associated with lung adenocarcinoma in the UK population. Cancer epidemiol biomarkers prev, Vol.20 (7), pp. 1453-1462. show abstract
BACKGROUND: Variation at TP63 has recently been shown to be associated with lung adenocarcinoma in the Asian population. METHODS: To investigate how this finding translates to the European population we compared the genotypes of SNPs annotating the TP63 locus at 3q28 in 4,462 lung cancer patients, including 911 with adenocarcinoma, and 8,235 controls from the United Kingdom. RESULTS: A statistically significant association between adenocarcinoma risk and SNP genotype was shown: rs10937405, OR = 1.21, P = 1.82 × 10(-4); rs17429138, OR = 1.23, P = 7.49 × 10(-5); and rs4396880, OR = 1.21, P = 2.03 × 10(-4). Haplotype analysis was consistent with a single TP63 risk locus defined by SNPs rs10937405, rs17429138, and rs4396880. While no association between SNPs and small cell lung cancer was shown, the rs10937405 and rs439680 associations were significant for squamous cancer (respective P-values, 0.0022 and 0.02). CONCLUSIONS: These findings show TP63 variation is a risk factor for the development of lung adenocarcinoma in the UK population. Furthermore, they provide additional insight into the subtype-specificity of the 3q28 lung cancer association. IMPACT: Our data confirm the association of 3q28 with lung adenocarcinoma and that this association is not confined to the Asian population. Elucidating the functional basis of this association will be contingent on future fine mapping of the TP63 loci..
Crowther-Swanepoel, D., Di Bernardo, M.C., Jamroziak, K., Karabon, L., Frydecka, I., Deaglio, S., D'Arena, G., Rossi, D., Gaidano, G., Olver, B., et al. (2011). Common genetic variation at 15q25 2 impacts on chronic lymphocytic leukaemia risk. Br j haematol, Vol.154 (2), pp. 229-233. show abstract
A genome-wide association study of chronic lymphocytic leukaemia (CLL) suggested that common variants at 15q25.2 (rs783540) and 18q21.1 (rs1036935) influence CLL. To validate these associations and explore their relationship with CLL risk we genotyped case-control datasets from Poland, UK and Italy totalling 1428 cases and 1920 controls. Combined data from these and previously genotyped series (2503 cases and 5789 controls) provided evidence for an association between 15q25.2 and 18q21.1 loci and CLL risk (P(combined) = 1·10 × 10(-7) and 1·30 × 10(-5) respectively). These data provide further evidence for the involvement of common genetic variants in CLL risk and insight into the biological basis of disease development..
Amirian, E.S., Scheurer, M.E., Liu, Y., D'Amelio, A.M., Houlston, R.S., Etzel, C.J., Shete, S., Swerdlow, A.J., Schoemaker, M.J., McKinney, P.A., et al. (2011). A novel approach to exploring potential interactions among single-nucleotide polymorphisms of inflammation genes in gliomagenesis: an exploratory case-only study. Cancer epidemiol biomarkers prev, Vol.20 (8), pp. 1683-1689. show abstract
BACKGROUND: Despite extensive research on the topic, glioma etiology remains largely unknown. Exploration of potential interactions between single-nucleotide polymorphisms (SNP) of immune genes is a promising new area of glioma research. The case-only study design is a powerful and efficient design for exploring possible multiplicative interactions between factors that are independent of one another. The purpose of our study was to use this exploratory design to identify potential pair wise SNP-SNP interactions from genes involved in several different immune-related pathways for investigation in future studies. METHODS: The study population consisted of two case groups: 1,224 histologic confirmed, non-Hispanic white glioma cases from the United States and a validation population of 634 glioma cases from the United Kingdom. Polytomous logistic regression, in which one SNP was coded as the outcome and the other SNP was included as the exposure, was utilized to calculate the ORs of the likelihood of cases simultaneously having the variant alleles of two different SNPs. Potential interactions were examined only between SNPs located in different genes or chromosomes. RESULTS: Using this data mining strategy, we found 396 significant SNP-SNP interactions among polymorphisms of immune-related genes that were present in both the U.S. and U.K. study populations. CONCLUSION: This exploratory study was conducted for the purpose of hypothesis generation, and thus has provided several new hypotheses that can be tested using traditional case-control study designs to obtain estimates of risk. IMPACT: This is the first study, to our knowledge, to take this novel approach to identifying SNP-SNP interactions relevant to glioma etiology..
Whiffin, N., Broderick, P., Lubbe, S.J., Pittman, A.M., Penegar, S., Chandler, I. & Houlston, R.S. (2011). MLH1-93G > A is a risk factor for MSI colorectal cancer. Carcinogenesis, Vol.32 (8), pp. 1157-1161. show abstract
The -93G > A (rs1800734) polymorphism within the core promoter region of the MutL homolog 1 (MLH1) gene has recently been proposed as a low penetrance variant for colorectal cancer (CRC). We evaluated the significance of rs1800734 on CRC risk by genotyping 10 409 CRC cases and 6965 controls. The per allele odds ratio (OR) for all CRC-associated MLH1-93G > A was 1.06 (P = 0.037). Using a subset of 3132 cases with known microsatellite instability (MSI) status, the risk was shown to be confined to microsatellite instability-high (MSI-H) CRC; OR = 1.39 (P = 1.45 × 10(-4)). A meta-analysis of our study and four smaller published studies (totalling 801 cases, 10 890 controls) provided for increased evidence of relationship between MLH1-93G > A and MSI-H CRC risk (P = 3.43 × 10(-12)). The impact of MLH1-93G > A on CRC risk was shown to be independent of the 14 low penetrance loci for CRC identified by recent genome-wide association studies. These data provide further evidence that MLH1-93G > A is a low-penetrance variant for CRC and support the proposition that MLH1-93G > A acts as marker for a somatic event defining a specific CRC subtype..
Orr, N., Cooke, R., Jones, M., Fletcher, O., Dudbridge, F., Chilcott-Burns, S., Tomczyk, K., Broderick, P., Houlston, R., Ashworth, A., et al. (2011). Genetic variants at chromosomes 2q35, 5p12, 6q25 1, 10q26 13, and 16q12 1 influence the risk of breast cancer in men. Plos genet, Vol.7 (9), p. e1002290. show abstract
Male breast cancer accounts for approximately 1% of all breast cancer. To date, risk factors for male breast cancer are poorly defined, but certain risk factors and genetic features appear common to both male and female breast cancer. Genome-wide association studies (GWAS) have recently identified common single nucleotide polymorphisms (SNPs) that influence female breast cancer risk; 12 of these have been independently replicated. To examine if these variants contribute to male breast cancer risk, we genotyped 433 male breast cancer cases and 1,569 controls. Five SNPs showed a statistically significant association with male breast cancer: rs13387042 (2q35) (odds ratio (OR) = 1.30, p = 7.98×10⁻⁴), rs10941679 (5p12) (OR = 1.26, p = 0.007), rs9383938 (6q25.1) (OR = 1.39, p = 0.004), rs2981579 (FGFR2) (OR = 1.18, p = 0.03), and rs3803662 (TOX3) (OR = 1.48, p = 4.04×10⁻⁶). Comparing the ORs for male breast cancer with the published ORs for female breast cancer, three SNPs--rs13387042 (2q35), rs3803662 (TOX3), and rs6504950 (COX11)--showed significant differences in ORs (p<0.05) between sexes. Breast cancer is a heterogeneous disease; the relative risks associated with loci identified to date show subtype and, based on these data, gender specificity. Additional studies of well-defined patient subgroups could provide further insight into the biological basis of breast cancer development..
Webb, E., Broderick, P., Lubbe, S., Chandler, I., Tomlinson, I. & Houlston, R.S. (2011). A genome-wide scan of 10 000 gene-centric variants and colorectal cancer risk. Eur j hum genet, Vol.19 (10), p. 1110.
Huang, X., Kushekhar, K., Nolte, I., Kooistra, W., Visser, L., Bouwman, I., Kouprie, N., Veenstra, R., van Imhoff, G., Olver, B., et al. (2011). Multiple HLA class I and II associations in classical Hodgkin lymphoma and EBV status defined subgroups. Blood, Vol.118 (19), pp. 5211-5217. show abstract
The pathogenesis of classical Hodgkin lymphoma (cHL) involves environmental and genetic factors. To explore the role of the human leukocyte antigen (HLA) genes, we performed a case-control genotyping study in 338 Dutch cHL patients and more than 5000 controls using a PCR-based sequence-specific oligonucleotide probe hybridization approach. HLA-A68 and HLA-DR11 (5) were significantly increased in the cHL patient population compared with the controls. Three class II associations were observed in the EBV(-) cHL population with an increase of HLA-DR15 (2) and a decrease of HLA-DR4 and HLA-DR7. Allele frequencies of HLA-A1, HLA-B37, and HLA-DR10 were significantly increased in the EBV(+) cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in whites. The allele frequency of HLA-A2 was significantly decreased in the EBV(+) cHL population. Sequence-specific oligonucleotide probe analysis revealed significant differences between EBV(+) and EBV(-) cHL patients for 19 probes that discriminate between HLA-A*01 and HLA-A*02. In conclusion, the HLA-A1 and HLA-A2 antigens and not specific single nucleotide variants shared by multiple alleles are responsible for the association with EBV(+) cHL. Furthermore, several new protective and predisposing HLA class I and II associations for the EBV(+), the EBV(-), and the entire cHL population were identified..
Wade, R., Di Bernardo, M.C., Richards, S., Rossi, D., Crowther-Swanepoel, D., Gaidano, G., Oscier, D.G., Catovsky, D. & Houlston, R.S. (2011). Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial. Haematologica, Vol.96 (10), pp. 1496-1503. show abstract
BACKGROUND: There is variability in the outcome of patients with chronic lymphocytic leukemia with apparently the same stage of disease. Identifying genetic variants that influence patients' outcome and response to treatment may provide important insights into the biology of the disease. DESIGN AND METHODS: We investigated the possibility that genetic variation influences outcome by conducting a genome-wide analysis of 346,831 single nucleotide polymorphisms in 356 patients entered into a phase III trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Genotypes were linked to individual patients' outcome data and response to chemotherapy. The association between genotype and progression-free survival was assessed by Cox regression analysis adjusting for treatment and clinicopathology. RESULTS: The strongest associations were shown for rs1949733 (ACOX3; P=8.22x10-7), rs1342899 (P=7.72×10(-7)) and rs11158493 (PPP2R5E; P=8.50×10(-7)). In addition, the 52 single nucleotide polymorphisms associated at P<10(-4) included rs438034 (CENPF; P=4.86×10(-6)), previously correlated with cancer progression, and rs2255235 (B2M; P=3.10×10(-5)) and rs2064501 (IL22RA2; P=4.81×10(-5)) which map to B-cell genes. CONCLUSIONS: Our findings provide evidence that genetic variation is a determinant of progression-free survival of patients with chronic lymphocytic leukemia. Specific associations warrant further analyses..
Pastorczak, A., Górniak, P., Sherborne, A., Hosking, F., Trelińska, J., Lejman, M., Szczepański, T., Borowiec, M., Fendler, W., Kowalczyk, J., et al. (2011). Role of 657del5 NBN mutation and 7p12 2 (IKZF1), 9p21 (CDKN2A), 10q21 2 (ARID5B) and 14q11 2 (CEBPE) variation and risk of childhood ALL in the Polish population. Leuk res, Vol.35 (11), pp. 1534-1536. show abstract
Recent studies have shown that SNPs mapping to 7p12.2 (IKZF1), 9p21 (CDKN2A), 10q21.2 (ARID5B), and 14q11.2 (CEBPE) and carrier status for recessively inherited Nijmegen Breakage syndrome (NBS) influence childhood acute lymphoblastic leukemia (ALL) risk. To examine these relationship, we analysed 398 ALL cases and 731 controls from Poland. Statistically significant association between genotype at 7p12.2 (IKZF1), 10q21.2 (ARID5B) and the NBS associated locus, 8q21.3 (NBN) and ALL risk was found; odds ratios (ORs), 1.34 (P=0.002), 1.33 (P=0.003), and 1325.21 (P=0.0028), respectively. These data provide further insights into the biological basis of ALL highlighting the existence of both common and rare disease susceptibility variants..
Berntsson, S.G., Wibom, C., Sjostrom, S., Henriksson, R., Brannstrom, T., Broholm, H., Johansson, C., Fleming, S.J., McKinney, P.A., Bethke, L., et al. (2011). Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas. Journal of neuro-oncology, Vol.105 (3), pp. 531-538.
Niittymäki, I., Tuupanen, S., Li, Y., Järvinen, H., Mecklin, J.-., Tomlinson, I.P., Houlston, R.S., Karhu, A. & Aaltonen, L.A. (2011). Systematic search for enhancer elements and somatic allelic imbalance at seven low-penetrance colorectal cancer predisposition loci. Bmc med genet, Vol.12, p. 23. show abstract
BACKGROUND: Common single-nucleotide polymorphisms (SNPs) in ten chromosomal loci have been shown to predispose to colorectal cancer (CRC) in genome-wide association studies. A plausible biological mechanism of CRC susceptibility associated with genetic variation has so far only been proposed for three loci, each pointing to variants that affect gene expression through distant regulatory elements. In this study, we aimed to gain insight into the molecular basis of seven low-penetrance CRC loci tagged by rs4779584 at 15q13, rs10795668 at 10p14, rs3802842 at 11q23, rs4444235 at 14q22, rs9929218 at 16q22, rs10411210 at 19q13, and rs961253 at 20p12. METHODS: Possible somatic gain of the risk allele or loss of the protective allele was studied by analyzing allelic imbalance in tumour and corresponding normal tissue samples of heterozygous patients. Functional variants were searched from in silico predicted enhancer elements locating inside the CRC-associating linkage-disequilibrium regions. RESULTS: No allelic imbalance targeting the SNPs was observed at any of the seven loci. Altogether, 12 SNPs that were predicted to disrupt potential transcription factor binding sequences were genotyped in the same population-based case-control series as the seven tagging SNPs originally. None showed association with CRC. CONCLUSIONS: The results of the allelic imbalance analysis suggest that the seven CRC risk variants are not somatically selected for in the neoplastic progression. The bioinformatic approach was unable to pinpoint cancer-causing variants at any of the seven loci. While it is possible that many of the predisposition loci for CRC are involved in control of gene expression by targeting transcription factor binding sites, also other possibilities, such as regulatory RNAs, should be considered..
Yu, H., Zhao, H., Wang, L.-., Han, Y., Wei, C.V., Amos, C.I., Rafnar, T., Sulem, P., Stefansson, K., Landi, M.T., et al. (2011). An analysis of single nucleotide polymorphisms of 125 DNA repair genes in the Texas genome-wide association study of lung cancer with a replication for the XRCC4 SNPs. Cancer research, Vol.71.
Carvajal-Carmona, L.G., Cazier, J.-., Jones, A.M., Howarth, K., Broderick, P., Pittman, A., Dobbins, S., Tenesa, A., Farrington, S., Prendergast, J., et al. (2011). Fine-mapping of colorectal cancer susceptibility loci at 8q23 3, 16q22 1 and 19q13 11: refinement of association signals and use of in silico analysis to suggest functional variation and unexpected candidate target genes. Human molecular genetics, Vol.20 (14), pp. 2879-2888.
Shete, S., Lau, C.C., Houlston, R.S., Claus, E.B., Barnholtz-Sloan, J., Lai, R., Il'yasova, D., Schildkraut, J., Sadetzki, S., Johansen, C., et al. (2011). Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium. Cancer res, Vol.71 (24), pp. 7568-7575. show abstract
Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma..
Sanson, M., Hosking, F.J., Shete, S., Zelenika, D., Dobbins, S.E., Ma, Y., Enciso-Mora, V., Idbaih, A., Delattre, J.-., Hoang-Xuan, K., et al. (2011). Chromosome 7p11 2 (EGFR) variation influences glioma risk. Hum mol genet, Vol.20 (14), pp. 2897-2904. show abstract
While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, P(c) = 7.72 × 10(-8) and 2.09 × 10(-8), respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk..
Hosking, F.J., Feldman, D., Bruchim, R., Olver, B., Lloyd, A., Vijayakrishnan, J., Flint-Richter, P., Broderick, P., Houlston, R.S. & Sadetzki, S., et al. (2011). Search for inherited susceptibility to radiation-associated meningioma by genomewide SNP linkage disequilibrium mapping. Br j cancer, Vol.104 (6), pp. 1049-1054. show abstract
BACKGROUND: Exposure to ionising radiation is a well-established risk factor for multiple types of tumours, including malignant brain tumours. In the 1950s, radiotherapy was used to treat Tinea Capitis (TC) in thousands of children, mostly of North-African and Middle Eastern origin, during the mass migration to Israel. The over-representation of radiation-associated meningioma (RAM) and other cancers in specific families provide support for inherited genetic susceptibility to radiation-induced cancer. METHODS: To test this hypothesis, we genotyped 15 families segregating RAM using high-density single-nucleotide polymorphism (SNP) arrays. Using the family-based association test (FBAT) programme, we tested each polymorphism and haplotype for an association with RAM. RESULTS: The strongest haplotype associations were attained at 18q21.1 (P=7.5 × 10(-5)), 18q21.31 (P=2.8 × 10(-5)) and 10q21.3 (P=1.6 × 10(-4)). Although associations were not formally statistically significant after adjustment for multiple testing, the 18q21.1 and 10q21.3 associations provide support for a variation in PIAS2, KATNAL2, TCEB3C, TCEB3CL and CTNNA3 genes as risk factors for RAM. CONCLUSION: These findings suggest that any underlying genetic susceptibility to RAM is likely to be mediated through the co-inheritance of multiple risk alleles rather than a single major gene locus determining radiosensitivity..
Ho, J.W., Choi, S.-., Lee, Y.-., Hui, T.C., Cherny, S.S., Garcia-Barceló, M.-., Carvajal-Carmona, L., Liu, R., To, S.-., Yau, T.-., et al. (2011). Replication study of SNP associations for colorectal cancer in Hong Kong Chinese. Br j cancer, Vol.104 (2), pp. 369-375. show abstract
BACKGROUND: Recent genome-wide association studies of colorectal cancer (CRC) have identified common single-nucleotide polymorphisms (SNPs) mapping to 10 independent loci that confer modest increased risk. These studies have been conducted in European populations and it is unclear whether these observations generalise to populations with different ethnicities and rates of CRC. METHODS: An association study was performed on 892 CRC cases and 890 controls recruited from the Hong Kong Chinese population, genotyping 32 SNPs, which were either associated with CRC in previous studies or are in close proximity to previously reported risk SNPs. RESULTS: Twelve of the SNPs showed evidence of an association. The strongest associations were provided by rs10795668 on 10p14, rs4779584 on 15q14 and rs12953717 on 18q21.2. There was significant linear association between CRC risk and the number of independent risk variants possessed by an individual (P=2.29 × 10(-5)). CONCLUSION: These results indicate that some previously reported SNP associations also impact on CRC risk in the Chinese population. Possible reasons for failure of replication for some loci include inadequate study power, differences in allele frequency, linkage disequilibrium structure or effect size between populations. Our results suggest that many associations for CRC are likely to generalise across populations..
Saarinen, S., Aavikko, M., Aittomäki, K., Launonen, V., Lehtonen, R., Franssila, K., Lehtonen, H.J., Kaasinen, E., Broderick, P., Tarkkanen, J., et al. (2011). Exome sequencing reveals germline NPAT mutation as a candidate risk factor for Hodgkin lymphoma. Blood, Vol.118 (3), pp. 493-498. show abstract
A strong clustering of Hodgkin lymphoma in certain families has been long acknowledged. However, the genetic factors in the background of familial Hodgkin lymphoma are largely unknown. We have studied a family of 4 cousins with a rare subtype of the disease, nodular lymphocyte predominant Hodgkin lymphoma. We applied exome sequencing together with genome-wide linkage analysis to this family and identified a truncating germline mutation in nuclear protein, ataxia-telangiectasia locus (NPAT) gene, which segregated in the family. We also studied a large number of samples from other patients with Hodgkin lymphoma, and a germline variation leading to the deletion of serine 724 was found in several cases suggesting an elevated risk for the disease (odds ratio = 4.11; P = .018). NPAT is thus far the first gene implicated in nodular lymphocyte predominant Hodgkin lymphoma predisposition..
Moutsianas, L., Enciso-Mora, V., Ma, Y.P., Leslie, S., Dilthey, A., Broderick, P., Sherborne, A., Cooke, R., Ashworth, A., Swerdlow, A.J., et al. (2011). Multiple Hodgkin lymphoma-associated loci within the HLA region at chromosome 6p21 3. Blood, Vol.118 (3), pp. 670-674. show abstract
Since an association between the human leukocyte antigen (HLA) region and Hodgkin lymphoma (HL) was first reported in 1967, many studies have reported associations between HL risk and both single nucleotide polymorphism (SNP) and classic HLA allele variation in the major histocompatibility complex. However, population stratification and the extent and complexity of linkage disequilibrium within the major histocompatibility complex have hindered efforts to fine-map causal signals. Using SNP data to impute alleles at classic HLA loci, we have conducted an integrated analysis of HL risk within the HLA region in 582 early-onset HL cases and 4736 controls. We confirm that the strongest signal of association comes from an SNP located in the class II region, rs6903608 (odds ratio [OR] = 1.79, P = 6.63 × 10(-19)), which is unlikely to be driven by association to HLA-DRB, DQA, or DQB alleles. In addition, we identify independent signals at rs2281389 (OR = 1.73, P = 6.31 × 10(-13)), a SNP that maps closely to HLA-DPB1, and the class II HLA allele DQA1*02:01 (OR = 0.56, P = 1.51 × 10(-7)). These data suggest that multiple independent loci within the HLA class II region contribute to the risk of developing early-onset HL..
Wang, Y., Broderick, P., Matakidou, A., Eisen, T. & Houlston, R.S. (2011). Chromosome 15q25 (CHRNA3-CHRNA5) variation impacts indirectly on lung cancer risk. Plos one, Vol.6 (4), p. e19085. show abstract
Genetic variants at the 15q25 CHRNA5-CHRNA3 locus have been shown to influence lung cancer risk however there is controversy as to whether variants have a direct carcinogenic effect on lung cancer risk or impact indirectly through smoking behavior. We have performed a detailed analysis of the 15q25 risk variants rs12914385 and rs8042374 with smoking behavior and lung cancer risk in 4,343 lung cancer cases and 1,479 controls from the Genetic Lung Cancer Predisposition Study (GELCAPS). A strong association between rs12914385 and rs8042374, and lung cancer risk was shown, odds ratios (OR) were 1.44, (95% confidence interval (CI): 1.29-1.62, P = 3.69×10(-10)) and 1.35 (95% CI: 1.18-1.55, P = 9.99×10(-6)) respectively. Each copy of risk alleles at rs12914385 and rs8042374 was associated with increased cigarette consumption of 1.0 and 0.9 cigarettes per day (CPD) (P = 5.18×10(-5) and P = 5.65×10(-3)). These genetically determined modest differences in smoking behavior can be shown to be sufficient to account for the 15q25 association with lung cancer risk. To further verify the indirect effect of 15q25 on the risk, we restricted our analysis of lung cancer risk to never-smokers and conducted a meta-analysis of previously published studies of lung cancer risk in never-smokers. Never-smoker studies published in English were ascertained from PubMed stipulating--lung cancer, risk, genome-wide association, candidate genes. Our study and five previously published studies provided data on 2,405 never-smoker lung cancer cases and 7,622 controls. In the pooled analysis no association has been found between the 15q25 variation and lung cancer risk (OR = 1.09, 95% CI: 0.94-1.28). This study affirms the 15q25 association with smoking and is consistent with an indirect link between genotype and lung cancer risk..
Dobbins, S.E., Broderick, P., Melin, B., Feychting, M., Johansen, C., Andersson, U., Brännström, T., Schramm, J., Olver, B., Lloyd, A., et al. (2011). Common variation at 10p12 31 near MLLT10 influences meningioma risk. Nat genet, Vol.43 (9), pp. 825-827. show abstract
To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development..
Huang, Z., Wang, J., Wu, C.-., Houlston, R.S., Bondy, M.L. & Shete, S. (2011). False-negative-rate based approach selecting top single-nucleotide polymorphisms in the first stage of a two-stage genome-wide association study. Statistics and its interface, Vol.4 (3), pp. 359-371.
Broderick, P., Chubb, D., Johnson, D.C., Weinhold, N., Försti, A., Lloyd, A., Olver, B., Ma, Y., Dobbins, S.E., Walker, B.A., et al. (2011). Common variation at 2p23 3 and 7p15 3 influences multiple myeloma risk. Nature genetics, Vol.Accepted for publication.
Hosking, F.J., Dobbins, S.E. & Houlston, R.S. (2011). Genome-wide association studies for detecting cancer susceptibility. Br med bull, Vol.97, pp. 27-46. show abstract
Genome-wide association (GWA) studies search for genetic variants, across the entire genome, which display differences in frequencies between cases and controls. Studies in PubMed using the keywords 'genomewide association' and 'cancer' are reported together with selected literature. Since 2007, GWA studies have successfully yielded risk loci for most common cancers. Findings have provided insights into the biological basis of cancer susceptibility implicating previously unsuspected genes in tumourogenesis. The variants identified typically account for only a small proportion of the familial risk of cancer and thus their application for individual risk prediction is poor. Furthermore, the genotyped variants are unlikely to be directly causal and identifying the causal basis is a major challenge. Methodological developments are desirable to fully utilize existing data sets and to enable more complex models of inherited predisposition to be investigated. Annotation of low frequency variation coupled with next-generation sequencing is making the search for rare disease-causing variants a realistic prospect..
Simon, M., Hosking, F.J., Marie, Y., Gousias, K., Boisselier, B., Carpentier, C., Schramm, J., Mokhtari, K., Hoang-Xuan, K., Idbaih, A., et al. (2010). Genetic risk profiles identify different molecular etiologies for glioma. Clin cancer res, Vol.16 (21), pp. 5252-5259. show abstract
PURPOSE: Genome-wide association studies have recently identified single-nucleotide polymorphisms (SNP) in five loci at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A/CDKN2B), 20q13.33 (rs6010620, RTEL1), and 11q23.3 (rs498872, PHLDB1) to be associated with glioma risk. Because gliomas are heterogeneous in histology, molecular alterations, and clinical behavior, we have investigated these polymorphisms for potential correlations with tumor histology and patient survival. EXPERIMENTAL DESIGN: We studied the relationship between SNPs and glioma subtype in two large patient cohorts from France and Germany, totaling 1,577 patients, as well as the relationship between SNP genotype and overall survival. RESULTS: In both cohorts, the frequencies of rs2736100 and rs6010620 risk genotypes were highly correlated with high-grade disease (P < 0.001), whereas rs4295627 and rs498872 risk genotypes were inversely related to tumor grade (P < 0.001). These data show that genetic variations at these loci have subtype-specific effects on the risk of developing glioma. In contrast, the rs4977756 genotype was not correlated with tumor grade, consistent with the causal variant having a generic influence on glioma development. None of the five SNPs was associated with prognosis independent of tumor grade. CONCLUSIONS: Our findings provide novel insight into etiologic pathways in the different glioma subtypes..
Schoemaker, M.J., Robertson, L., Wigertz, A., Jones, M.E., Hosking, F.J., Feychting, M., Lönn, S., McKinney, P.A., Hepworth, S.J., Muir, K.R., et al. (2010). Interaction between 5 genetic variants and allergy in glioma risk. Am j epidemiol, Vol.171 (11), pp. 1165-1173. show abstract
The etiology of glioma is barely known. Epidemiologic studies have provided evidence for an inverse relation between glioma risk and allergic disease. Genome-wide association data have identified common genetic variants at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A-CDKN2B), 11q23.3 (rs498872, PHLDB1), and 20q13.33 (rs6010620, RTEL1) as determinants of glioma risk. The authors investigated whether there is interaction between the effects of allergy and these 5 variants on glioma risk. Data from 5 case-control studies carried out in Denmark, Finland, Sweden, and the United Kingdom (2000-2004) were used, totaling 1,029 cases and 1,668 controls. Risk was inversely associated with asthma, hay fever, eczema, and "any allergy," significantly for each factor except asthma, and was significantly positively associated with number of risk alleles for each of the 5 single nucleotide polymorphisms. There was interaction between asthma and rs498872 (greater protective effect of asthma with increasing number of risk alleles; per-allele interaction odds ratio (OR) = 0.65, P = 0.041), between "any allergy" and rs4977756 (smaller protective effect; interaction OR = 1.27, P = 0.047), and between "any allergy" and rs6010620 (greater protective effect; interaction OR = 0.70, P = 0.017). Case-only analyses provided further support for atopy interactions for rs4977756 and rs498872. This study provides evidence for possible gene-environment interactions in glioma development..
Crowther-Swanepoel, D., Broderick, P., Ma, Y., Robertson, L., Pittman, A.M., Price, A., Twiss, P., Vijayakrishnan, J., Qureshi, M., Dyer, M.J., et al. (2010). Fine-scale mapping of the 6p25 3 chronic lymphocytic leukaemia susceptibility locus. Hum mol genet, Vol.19 (9), pp. 1840-1845. show abstract
A recent genome-wide association study of chronic lymphocytic leukaemia (CLL) has identified a susceptibility locus on 6p25.3 associated with a modest but highly significant increase in CLL risk. Using a set of single nucleotide polymorphism (SNP) markers, we generated a fine-scale map and narrowed the association signal to a 18 kb DNA segment within the 3'-untranslated region (UTR) of the IRF4 (interferon regulatory factor 4) gene. Resequencing this segment in European subjects identified 55 common polymorphisms, including 13 highly correlated candidate causal variants. In a large case-control study, it was shown that all but four variants could be excluded with 95% confidence. These four SNPs map to a 3 kb region of the 3'-UTR of IRF4, consistent with the causal basis of the association being mediated through differential IRF4 expression..
Broderick, P., Cunningham, D., Vijayakrishnan, J., Cooke, R., Ashworth, A., Swerdlow, A. & Houlston, R. (2010). IRF4 polymorphism rs872071 and risk of Hodgkin lymphoma. Brit j haematol, Vol.148 (3), pp. 413-415. show abstract
P>The reciprocal familial risk between chronic lymphocytic leukaemia (CLL) and Hodgkin lymphoma (HL) suggests genetic variants with pleiotropic effects may influence the risk of both CLL and HL. We have recently shown that the IRF4 variant rs872071 influences CLL risk. To examine if rs872071 genotype is associated with HL risk we genotyped two case-control series (totalling, 529 and 2192, respectively). This analysis provides evidence that IRF4 rs872071 influences HL risk; Odds Ratio = 1 center dot 21 (95% confidence interval: 1 center dot 05-1 center dot 39, P = 0 center dot 009) and highlights the importance of inherited variation in B-cell developmental genes in the development of HL..
Crowther-Swanepoel, D., Broderick, P., Di Bernardo, M.C., Dobbins, S.E., Torres, M., Mansouri, M., Ruiz-Ponte, C., Enjuanes, A., Rosenquist, R., Carracedo, A., et al. (2010). Common variants at 2q37 3, 8q24 21, 15q21 3 and 16q24 1 influence chronic lymphocytic leukemia risk. Nat genet, Vol.42 (2), pp. 132-136. show abstract
To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.39; P = 2.11 x 10(-9)), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 x 10(-10)), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 x 10(-7)) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 x 10(-7)). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 x 10(-6)) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 x 10(-6)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy..
Wang, Y., Broderick, P., Matakidou, A., Eisen, T. & Houlston, R.S. (2010). Role of 5p15 33 (TERT-CLPTM1L), 6p21 33 and 15q25 1 (CHRNA5-CHRNA3) variation and lung cancer risk in never-smokers. Carcinogenesis, Vol.31 (2), pp. 234-238. show abstract
Genome-wide association studies have provided evidence that common variation at 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) influences lung cancer risk. To examine if variation at any of these loci influences the risk of lung cancer in never-smokers, we compared 5p15.33-TERT (rs2736100), 5p15.33-CLPTM1L (rs4975616), 6p21.33-BAT3 (rs3117582), 15q25.1-CHRNA3 (rs8042374) and 15q25.1-CHRNA3 (rs12914385) genotypes in a series of 239 never-smoker lung cancer cases and 553 never-smoker controls. A statistically significant association between lung cancer risk and 5p15.33 genotypes was found: rs2736100 (odds ratio = 0.78, 95% confidence interval: 0.63-0.97; P = 0.02), rs4975616 (odds ratio = 0.69, 95% confidence interval: 0.55-0.85; P = 7.95 x 10(-4)), primarily for adenocarcinoma. There was no evidence of association between 6p21.33 or 15q25.1 variation and risk of lung cancer. This analysis provides evidence that TERT-CLPTM1L variants may influence the risk of lung cancer outside the context of tobacco smoking..
Hosking, F.J., Papaemmanuil, E., Sheridan, E., Kinsey, S.E., Lightfoot, T., Roman, E., Irving, J.A., Allan, J.M., Taylor, M., Tomlinson, I.P., et al. (2010). Genome-wide homozygosity signatures and childhood acute lymphoblastic leukemia risk. Blood, Vol.115 (22), pp. 4472-4477. show abstract
Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we analyzed 824 ALL cases and 2398 controls genotyped for 292 200 tagging SNPs. Across the genome, cumulative distribution of ROH was not significantly different between cases and controls. Four common ROH at 10p11.2-10q11.21, 1p31.1, 19p13.2-3, and 20q11.1-23 were, however, associated with ALL risk at P less than .01 (including 1 ROH to which the erythropoietin receptor [EPOR] gene maps, P = .005) but were nonsignificant after adjusting for multiple testing. Our findings make it unlikely that levels of measured homozygosity, caused by autozygosity, uniparental isodisomy, or hemizygosity, play a major role in defining BCP-ALL risk in predominantly outbred populations..
Liu, Y., Shete, S., Hosking, F.J., Robertson, L.B., Bondy, M.L. & Houlston, R.S. (2010). New insights into susceptibility to glioma. Arch neurol, Vol.67 (3), pp. 275-278. show abstract
The study of inherited susceptibility to cancer has been one of the most informative areas of research in the past decade. Most of the cancer genetics studies have been focused on the common tumors such as breast and colorectal cancers. As the allelic architecture of these tumors is unraveled, research attention is turning to other rare cancers such as glioma, which are also likely to have a major genetic component as the basis of their development. In this brief review we discuss emerging data on glioma whole genome-association searches to identify risk loci. Two glioma genome-wide association studies have so far been reported. Our group identified 5 risk loci for glioma susceptibility (TERT rs2736100, CCDC26 rs4295627, CDKN2A/CDKN2B rs4977756, RTEL1 rs6010620, and PHLDB1 rs498872). Wrensch and colleagues provided further evidence to 2 risk loci (CDKN2B rs1412829 and RTEL1 rs6010620) for GBM and anaplastic astrocytoma. Although these data provide the strongest evidence to date for the role of common low-risk variants in the etiology of glioma, the single-nucleotide polymorphisms identified alone are unlikely to be candidates for causality. Identifying the causal variant at each specific locus and its biological impact now poses a significant challenge, contingent on a combination of fine mapping and functional analyses. Finally, we hope that a greater understanding of the biological basis of the disease will lead to the development of novel therapeutic interventions..
White, S.M., Morgan, A., Da Costa, A., Lacombe, D., Knight, S.J., Houlston, R., Whiteford, M.L., Newbury-Ecob, R.A. & Hurst, J.A. (2010). The Phenotype of Floating-Harbor Syndrome in 10 Patients. American journal of medical genetics part a, Vol.152A (4), pp. 821-829.
Allan, J.M., Sunter, N.J., Bailey, J.R., Pettitt, A.R., Harris, R.J., Pepper, C., Fegan, C., Hall, A.G., Deignan, L., Bacon, C.M., et al. (2010). Variant IRF4/MUM1 associates with CD38 status and treatment-free survival in chronic lymphocytic leukaemia. Leukemia, Vol.24 (4), pp. 877-881.
Prasad, R.B., Hosking, F.J., Vijayakrishnan, J., Papaemmanuil, E., Koehler, R., Greaves, M., Sheridan, E., Gast, A., Kinsey, S.E., Lightfoot, T., et al. (2010). Verification of the susceptibility loci on 7p12 2, 10q21 2, and 14q11 2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood, Vol.115 (9), pp. 1765-1767. show abstract
Recent genome-wide association data have implicated genetic variation at 7p12.2 (IKZF1), 10q21.2 (ARIDB5), and 14q11.2 (CEBPE) in the etiology of B-cell childhood acute lymphoblastic leukemia (ALL). To verify and further examine the relationship between these variants and ALL risk, we genotyped 1384 cases of precursor B-cell childhood ALL and 1877 controls from Germany and the United Kingdom. The combined data provided statistically significant support for an association between genotype at each of these loci and ALL risk; odds ratios (OR), 1.69 (P = 7.51 x10(-22)), 1.80 (P = 5.90 x 10(-28)), and 1.27 (P = 4.90 x 10(-6)), respectively. Furthermore, the risk of ALL increases with an increasing numbers of variant alleles for the 3 loci (OR(per-allele) = 1.53, 95% confidence interval, 1.44-1.62; P(trend) = 3.49 x 10(-42)), consistent with a polygenic model of disease susceptibility. These data provide unambiguous evidence for the role of these variants in defining ALL risk underscoring approximately 64% of cases..
Fletcher, O. & Houlston, R.S. (2010). Architecture of inherited susceptibility to common cancer. Nat rev cancer, Vol.10 (5), pp. 353-361. show abstract
This Timeline article looks back at 40 years of research into the inherited genetic basis of cancer and the insights these studies have yielded. Early epidemiological research provided evidence for the 'two-hit' model of cancer predisposition. During the 1980s and 1990s linkage and positional cloning analyses led to the identification of high-penetrance cancer susceptibility genes. The past decade has seen a shift from models of predisposition based on single-gene causative mutations to multigenic models. These models suggest that a high proportion of cancers may arise in a genetically susceptible minority as a consequence of the combined effects of common low-penetrance alleles and rare disease-causing variants that confer moderate cancer risks..
Vahteristo, P., Koski, T.A., Naatsaari, L., Kiuru, M., Karhu, A., Herva, R., Sallinen, S.-., Vierimaa, O., Bjorck, E., Richard, S., et al. (2010). No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome. Familial cancer, Vol.9 (2), pp. 245-251.
Middeldorp, A., Jagmohan-Changur, S.C., van der Klift, H.M., van Puijenbroek, M., Houwing-Duistermaat, J.J., Webb, E., Houlston, R., Tops, C., Vasen, H.F., Devilee, P., et al. (2010). Comprehensive Genetic Analysis of Seven Large Families with Mismatch Repair Proficient Colorectal Cancer. Genes chromosomes & cancer, Vol.49 (6), pp. 539-548.
Liu, Y., Shete, S., Hosking, F., Robertson, L., Houlston, R. & Bondy, M. (2010). Genetic advances in glioma: susceptibility genes and networks. Current opinion in genetics & development, Vol.20 (3), pp. 239-244.
Turnbull, C., Ahmed, S., Morrison, J., Pernet, D., Renwick, A., Maranian, M., Seal, S., Ghoussaini, M., Hines, S., Healey, C.S., et al. (2010). Genome-wide association study identifies five new breast cancer susceptibility loci. Nat genet, Vol.42 (6), pp. 504-507. show abstract
Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 x 10(-7) to P = 3.2 x 10(-15)). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 x 10(-6)), 8q24 (rs1562430, P = 5.8 x 10(-7)) and LSP1 (rs909116, P = 7.3 x 10(-7)) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease..
Niittymäki, I., Kaasinen, E., Tuupanen, S., Karhu, A., Järvinen, H., Mecklin, J.-., Tomlinson, I.P., Di Bernardo, M.C., Houlston, R.S. & Aaltonen, L.A., et al. (2010). Low-penetrance susceptibility variants in familial colorectal cancer. Cancer epidemiol biomarkers prev, Vol.19 (6), pp. 1478-1483. show abstract
BACKGROUND: Genomewide association studies have identified 10 low-penetrance loci that confer modestly increased risk for colorectal cancer (CRC). Although they underlie a significant proportion of CRC in the general population, their impact on the familial risk for CRC has yet to be formally enumerated. The aim of this study was to examine the combined contribution of the 10 variants, rs6983267, rs4779584, rs4939827, rs16892766, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, on familial CRC. METHODS: The population-based series of CRC samples included in this study consisted of 97 familial cases and 691 sporadic cases. Genotypes in the 10 loci and clinical data, including family history of cancer verified from the Finnish Cancer Registry, were available. The overall number of risk alleles (0-20) was determined, and its association with familial CRC was analyzed. Excess familial risk was estimated using cancer incidence data from the first-degree relatives of the cases. RESULTS: A linear association between the number of risk alleles and familial CRC was observed (P = 0.006). With each risk-allele addition, the odds of having an affected first-degree relative increased by 1.16 (95% confidence interval, 1.04-1.30). The 10 low-penetrance loci collectively explain approximately 9% of the variance in familial risk for CRC. CONCLUSIONS: This study provides evidence to support the previous indirect estimations that these low-penetrance variants account for a relatively small proportion of the familial aggregation of CRC. IMPACT: Our results emphasize the need to characterize the remaining molecular basis of familial CRC, which should eventually yield in individualized targeting of preventive interventions..
Sherborne, A.L., Hosking, F.J., Prasad, R.B., Kumar, R., Koehler, R., Vijayakrishnan, J., Papaemmanuil, E., Bartram, C.R., Stanulla, M., Schrappe, M., et al. (2010). Variation in CDKN2A at 9p21 3 influences childhood acute lymphoblastic leukemia risk. Nat genet, Vol.42 (6), pp. 492-494. show abstract
Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 x 10(-11)), irrespective of cell lineage..
Houlston, R.S. (2010). Low-penetrance susceptibility to hematological malignancy. Curr opin genet dev, Vol.20 (3), pp. 245-250. show abstract
There is increasing evidence for inherited genetic susceptibility to cancer, and much of this is thought to be caused by the co-inheritance of multiple low risk alleles. Recent developments have allowed the search for this class of susceptibility allele to be conducted on a genome-wide basis. Here we discuss the impact genome-wide association studies are having on our understanding of two of the major hematological malignancies, chronic lymphocytic leukemia and acute lymphoblastic leukemia..
Theodoratou, E., Campbell, H., Tenesa, A., Houlston, R., Webb, E., Lubbe, S., Broderick, P., Gallinger, S., Croitoru, E.M., Jenkins, M.A., et al. (2010). A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. British journal of cancer, Vol.103 (12), pp. 1875-1884.
Bancroft, E.K., Locke, I., Ardern-Jones, A., D'Mello, L., McReynolds, K., Lennard, F., Barbachano, Y., Barwell, J., Walker, L., Mitchell, G., et al. (2010). The carrier clinic: an evaluation of a novel clinic dedicated to the follow-up of BRCA1 and BRCA2 carriers--implications for oncogenetics practice. J med genet, Vol.47 (7), pp. 486-491. show abstract
BACKGROUND: A novel oncogenetic clinic was established in 2002 at the Royal Marsden NHS Foundation Trust offering advice and specialist follow-up for families with a germline mutation in BRCA1 or BRCA2. The remit of this multidisciplinary clinic, staffed by individuals in both oncology and genetics, is to provide individualised screening recommendations, support in decision making, risk reducing strategies, cascade testing, and an extensive research portfolio. METHODS: A retrospective analysis was performed to evaluate uptake of genetic testing, risk reducing surgery and cancer prevalence in 346 BRCA1/BRCA2 families seen between January 1996 and December 2006. RESULTS: 661 individuals attended the clinic and 406 mutation carriers were identified; 85.8% mutation carriers have chosen to attend for annual follow-up. 70% of mutation carriers elected for risk reducing bilateral salpingo-oophorectomy (RRBSO). 32% of unaffected women chose risk reducing bilateral mastectomy. 32% of women with breast cancer chose contralateral risk reducing mastectomy at time of diagnosis. Some women took over 8 years to decide to have surgery. 91% of individuals approached agreed to participate in research programmes. INTERPRETATION: A novel specialist clinic for BRCA1/2 mutation carriers has been successfully established. The number of mutation positive families is increasing. This, and the high demand for RRBSO in women over 40, is inevitably going to place an increasing demand on existing health resources. Our clinic model has subsequently been adopted in other centres and this will greatly facilitate translational studies and provide a healthcare structure for management and follow-up of such people who are at a high cancer risk..
Saccone, N.L., Culverhouse, R.C., Schwantes-An, T.-., Cannon, D.S., Chen, X., Cichon, S., Giegling, I., Han, S., Han, Y., Keskitalo-Vuokko, K., et al. (2010). Multiple Independent Loci at Chromosome 15q25 1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD. Plos genetics, Vol.6 (8).
Landi, M.T., Chatterjee, N., Caporaso, N.E., Rotunno, M., Albanes, D., Thun, M., Wheeler, W., Rosenberger, A., Bickeböller, H., Risch, A., et al. (2010). GPC5 rs2352028 variant and risk of lung cancer in never smokers. Lancet oncol, Vol.11 (8), pp. 714-716.
Crowther-Swanepoel, D., Mansouri, M., Enjuanes, A., Vega, A., Smedby, K.E., Ruiz-Ponte, C., Jurlander, J., Juliusson, G., Montserrat, E., Catovsky, D., et al. (2010). Verification that common variation at 2q37 1, 6p25 3, 11q24 1, 15q23, and 19q13 32 influences chronic lymphocytic leukaemia risk. Br j haematol, Vol.150 (4), pp. 473-479. show abstract
A recent genome wide association study of chronic lymphocytic leukaemia (CLL) provided evidence that common variation at 2q13 (rs17483466), 2q37.1 (rs13397985), 6p25.3 (rs872071), 11q24.1 (rs735665), 15q23 (rs7176508) and 19q13.32 (rs11083846) affects CLL risk. To verify and further explore the relationship between these variants and CLL risk we genotyped case-control datasets from Spain and Sweden (824 cases, 850 controls). Combined data provided statistically significant support for an association between genotypes at rs13397985, rs872071, rs735665, rs7176508 and rs11083846 and CLL risk. CLL risk increased with increasing numbers of risk alleles (P(trend) = 1.40 x 10(-15)), consistent with a polygenic model of disease susceptibility. These data validate the relationship between common variation and risk of CLL..
Vijayakrishnan, J. & Houlston, R.S. (2010). Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Haematologica, Vol.95 (8), pp. 1405-1414. show abstract
To evaluate the contribution of candidate gene association studies to the understanding of genetic susceptibility to childhood acute lymphoblastic leukemia we conducted a systematic review and meta-analysis of published studies (January 1996-July 2009). Studies had to meet the following criteria: be case-control design, be studied by two or more studies, not be focused on HLA antigen genetic markers and be published in English. We identified 47 studies of polymorphic variation in 16 genes and acute lymphoblastic leukemia risk. To clarify the impact of individual polymorphisms on risk, pooled analyses were performed. Of the 25 polymorphic variants studied, significant associations (P<0.05) were seen in pooled analyses for eight variants: GSTM1 (OR =1.16; 95%CI: 1.04-1.30), MTRR A66G (OR=0.73, 95%CI:0.59-0.91), SHMT1 C1420T (OR=0.79, 95%CI: 0.65-0.98), RFC1 G80A (OR=1.37, 95%CI: 1.11-1.69), CYP1A1*2A (OR=1.36, 95%CI:1.11-1.66), CYP2E1*5B (OR=1.99, 95%CI:1.32-3.00) NQO1 C609T (OR=1.24, 95%CI:1.02-1.50) and XRCC1 G28152A (OR=1.78, 95%CI:1.32-2.42). These findings should, however, be interpreted with caution as the estimated false-positive report probabilities (FPRP) for each association were not noteworthy (i.e. FPRP>0.2). While candidate gene analyses are complementary to genome-wide association studies, future analyses should be based on sample sizes commensurate with the detection of small effects and attention needs to be paid to study design..
Enciso-Mora, V., Hosking, F.J. & Houlston, R.S. (2010). Risk of breast and prostate cancer is not associated with increased homozygosity in outbred populations. Eur j hum genet, Vol.18 (8), pp. 909-914. show abstract
Regions of restricted genetic heterogeneity due to identity by descent (autozygosity) are known to confer susceptibility to a number of diseases. Regions of germline homozygosity (ROHs) of 1-2 Mb, the result of autozygosity, are detectable at high frequency in outbred populations. Recent studies have reported that ROHs, possibly through exposing recessive disease-causing alleles or alternative mechanisms, are associated with an increased cancer risk. To examine whether homozygosity is associated with breast or prostate cancer risk, we analysed 500K single-nucleotide polymorphism data from two genome-wide association studies conducted by the Cancer Genetics Markers of Susceptibility initiatives (http://cgems.cancer.gov/). Six common ROHs were associated with breast cancer risk and four with prostate cancer (P<0.01). Intriguingly, one of the breast cancer ROHs maps to 6q22.31-6q22.3, a region that has been previously shown to confer breast cancer risk. Although none of the ROHs remained significantly associated with cancer risk after adjustment for multiple testing, a number of ROHs merit further interrogation. However, our findings provide no strong evidence that levels of measured homozygosity, whatever their aetiology (autozygosity, uniparental isodisomy or hemizygosity), confer an increased risk of developing breast or prostate cancer in predominantly outbred populations..
Sherborne, A.L. & Houlston, R.S. (2010). What are genome-wide association studies telling us about B-cell tumor development?. Oncotarget, Vol.1 (5), pp. 367-372. show abstract
It has long been speculated that common genetic variation influences the development of B-cell malignancy, however until recently evidence for this assertion was lacking. The advent of genome-wide association studies (GWAS) has allowed the search for this class of susceptibility allele to be conducted on a genome-wide basis. Recent GWAS of chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL) have identified novel disease genes for CLL and ALL and underscore the importance of polymorphic variation in B-cell development genes as determinants of leukemia risk..
Yilmaz, A., Hamel, N., Schwartz, C.E., Houlston, R.S., Harper, J.I. & Foulkes, W.D. (2010). A genome-wide analysis of loss of heterozygosity and chromosomal copy number variation in Proteus syndrome using high-density SNP microarrays. J hum genet, Vol.55 (9), pp. 627-630. show abstract
Excessive cell proliferation and genetic changes such as loss of an allele (loss of heterozygosity (LOH)) or amplifications or deletions of parts of chromosomes (copy number variations (CNV)) are common findings in cancers. It is unknown whether these changes are also present in patients with overgrowth syndromes, although the presence of small-scale CNVs (such as duplication of 11p15 in Beckwith-Wiedemann syndrome), excessive cell proliferation and an increased frequency of tumors have all been reported in these patients. We present results of a genome-wide scan for LOH and CNV in Proteus syndrome (PS), a severely disfiguring overgrowth syndrome. We investigated CNV and LOH in DNA derived from affected and normal tissue samples from six PS patients using Affymetrix GeneChip Mapping 250 K Nsp high-density single-nucleotide polymorphism microarrays. Analysis revealed that LOH and CNVs were not common in PS. We attempted to validate selected CNVs detected by microarray analysis using quantitative genomic PCR, but the observed changes were not confirmed. These results suggest that large-scale genome-wide CNVs and LOH as seen in cancer syndromes are not characteristic findings in PS, although we cannot rule out the possibility that newer arrays with a higher number of probes could uncover smaller CNVs not detected in this study..
Robertson, L.B., Armstrong, G.N., Olver, B.D., Lloyd, A.L., Shete, S., Lau, C., Claus, E.B., Barnholtz-Sloan, J., Lai, R., Il'yasova, D., et al. (2010). Erratum to: Survey of familial glioma and role of germline p16 ( INK4A )/p14 ( ARF ) and p53 mutation. Fam cancer, .
Robertson, L.B., Armstrong, G.N., Olver, B.D., Lloyd, A.L., Shete, S., Lau, C., Claus, E.B., Barnholtz-Sloan, J., Lai, R., Il'yasova, D., et al. (2010). Survey of familial glioma and role of germline p16INK4A/p14ARF and p53 mutation. Fam cancer, Vol.9 (3), pp. 413-421. show abstract
There is increasing recognition of familial propensity to glioma as a distinct clinical entity beyond a few rare syndromes; however its genetic basis is poorly understood. The role of p16(INK4A)/p14(ARF) and p53 mutations in sporadic glioma provides a strong rationale for investigating germline mutations in these genes as a cause of familial glioma. To survey the familial glioma phenotype and examine the contribution of germline mutation in p16(INK4A)/p14(ARF) and p53 to the disease we have analyzed a series of 101 index familial cases collected through the GLIOGENE Consortium (http://braintumor.epigenetic.org/). There was little evidence for within family correlations for tumour histology, suggesting generic susceptibility to glial tumors. We did not detect any functional mutations in p16(INK4A) or p14(ARF). One index case with glioblastoma multiforme (GBM) diagnosed at age 54 and had a family history comprised of a paternal aunt with GBM at age 55, carried the p53 R158H mutation, which is predicted to be functional and has previously been implicated as a cause of Li-Fraumeni syndrome. Our findings provide no evidence that p16(INK4A)/p14(ARF) and p53 mutations contribute significantly to familial glioma..
Liu, Y., Shete, S., Etzel, C.J., Scheurer, M., Alexiou, G., Armstrong, G., Tsavachidis, S., Liang, F.-., Gilbert, M., Aldape, K., et al. (2010). Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 Genes Involved in the Double-Strand Break Repair Pathway Predict Glioblastoma Survival. Journal of clinical oncology, Vol.28 (14), pp. 2467-2474.
Goode, E.L., Chenevix-Trench, G., Song, H., Ramus, S.J., Notaridou, M., Lawrenson, K., Widschwendter, M., Vierkant, R.A., Larson, M.C., Kjaer, S.K., et al. (2010). A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat genet, Vol.42 (10), pp. 874-879. show abstract
Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P ≤ 10⁻⁴) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P ≤ 5 × 10⁻⁸ (8q24, P = 8.0 × 10⁻¹⁵ and 2q31, P = 3.8 × 10⁻¹⁴) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10⁻⁸ and 17q21, P = 1.4 × 10⁻⁷). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development..
Bolton, E.L., Tyrer, J., Song, H., Ramus, S.J., Notaridou, M., Jones, C., Sher, T., Gentry-Maharaj, A., Wozniak, E., Tsai, Y.Y., et al. (2010). Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat genet, Vol.42 (10), pp. 880-+. show abstract
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women(1). We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 x 10(-4) and P = 6 x 10(-4), respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 x 10(-9) and P = 4 x 10(-11), respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development..
Vijayakrishnan, J., Sherborne, A.L., Sawangpanich, R., Hongeng, S., Houlston, R.S. & Pakakasama, S. (2010). Variation at 7p12 2 and 10q21 2 influences childhood acute lymphoblastic leukemia risk in the Thai population and may contribute to racial differences in leukemia incidence. Leuk lymphoma, Vol.51 (10), pp. 1870-1874. show abstract
Recent genome-wide association (GWA) studies of childhood acute lymphoblastic leukemia (ALL) have identified 7p12.2, 9p21.3, 10q21.2, and 14q11.2 SNPs that confer modest risks of ALL. These studies have been conducted in European populations, and it is unclear whether these observations generalize to other populations with a lower incidence of ALL. To explore the impact of these variants on ALL risk in the Thai population, we genotyped 190 cases of ALL and 182 controls for SNPs rs4132601 (7p12.2), rs3731217 (9p21.3), rs7089424 and rs10821938 (10q21.2), and rs2239633 (14q11.2). Consistent with findings in European populations, rs4132601 genotype was significantly associated with risk of ALL (odds ratio [OR] = 1.57, 95% confidence interval [CI]: 1.01-2.44; p = 0.04), and rs10821938 genotype was significantly associated with B-cell precursor ALL (OR = 0.73, 95% CI: 0.55-0.97; p = 0.03). There were, however, differences in allele frequencies in SNPs observed between Thai and Caucasian populations (e.g. IKZF1, rs4132601; risk allele frequency [RAF] ratio of 0.36 for Thai/Caucasian). These differences, combined with differences in linkage disequilibrium structure between populations or differences in effect size between populations, may contribute to racial differences in ALL incidence..
Schwartzbaum, J.A., Xiao, Y., Liu, Y., Tsavachidis, S., Berger, M.S., Bondy, M.L., Chang, J.S., Chang, S.M., Decker, P.A., Ding, B., et al. (2010). Inherited variation in immune genes and pathways and glioblastoma risk. Carcinogenesis, Vol.31 (10), pp. 1770-1777. show abstract
To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻⁵ to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk..
Houlston, R.S., Cheadle, J., Dobbins, S.E., Tenesa, A., Jones, A.M., Howarth, K., Spain, S.L., Broderick, P., Domingo, E., Farrington, S., et al. (2010). Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26 2, 12q13 13 and 20q13 33. Nat genet, Vol.42 (11), pp. 973-977. show abstract
Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10⁻¹⁰ and rs6687758, OR = 1.09, P = 2.27 × 10⁻⁹, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10⁻⁸), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10⁻¹⁰ and rs7136702, OR = 1.06, P = 4.02 × 10⁻⁸) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10⁻¹⁰). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered..
Enciso-Mora, V., Broderick, P., Ma, Y., Jarrett, R.F., Hjalgrim, H., Hemminki, K., van den Berg, A., Olver, B., Lloyd, A., Dobbins, S.E., et al. (2010). A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16 1 (REL), 8q24 21 and 10p14 (GATA3). Nat genet, Vol.42 (12), pp. 1126-1130. show abstract
To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10(-8)), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10(-13)) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10(-8)). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10(-50)). These data provide new insight into the pathogenesis of cHL..
Crowther-Swanepoel, D. & Houlston, R.S. (2010). Genetic variation and risk of chronic lymphocytic leukaemia. Semin cancer biol, Vol.20 (6), pp. 363-369. show abstract
Chronic lymphocytic leukaemia (CLL) is the most common form of lymphoid malignancy in Western countries, accounting for around a quarter of all leukaemias. Evidence from epidemiological and family studies have provided evidence for familial clustering of CLL compatible with inherited genetic predisposition to CLL. Direct evidence for genetic susceptibility has been provided by a recent genome wide association study of CLL which has identified common variants at 10 different loci which influence CLL risk. Here we review the current knowledge regarding the allelic architecture of susceptibility to CLL and what the currently identified risk loci are telling us regarding disease aetiology..
Pittman, A.M., Naranjo, S., Jalava, S.E., Twiss, P., Ma, Y., Olver, B., Lloyd, A., Vijayakrishnan, J., Qureshi, M., Broderick, P., et al. (2010). Allelic variation at the 8q23 3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H. Plos genet, Vol.6 (9), p. e1001126. show abstract
Common genetic variation at human 8q23.3 is significantly associated with colorectal cancer (CRC) risk. To elucidate the basis of this association we compared the frequency of common variants at 8q23.3 in 1,964 CRC cases and 2,081 healthy controls. Reporter gene studies showed that the single nucleotide polymorphism rs16888589 acts as an allele-specific transcriptional repressor. Chromosome conformation capture (3C) analysis demonstrated that the genomic region harboring rs16888589 interacts with the promoter of gene for eukaryotic translation initiation factor 3, subunit H (EIF3H). We show that increased expression of EIF3H gene increases CRC growth and invasiveness thereby providing a biological mechanism for the 8q23.3 association. These data provide evidence for a functional basis for the non-coding risk variant rs16888589 at 8q23.3 and provides novel insight into the etiological basis of CRC..
Tomlinson, I.P., Dunlop, M., Campbell, H., Zanke, B., Gallinger, S., Hudson, T., Koessler, T., Pharoah, P.D., Niittymaki, I., Tuupanen, S., et al. (2010). COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer (vol 102, pg 447, 2010). Brit j cancer, Vol.102 (2), pp. 455-455.
Tomlinson, I.P., Dunlop, M., Campbell, H., Zanke, B., Gallinger, S., Hudson, T., Koessler, T., Pharoah, P.D., Niittymäki, I., Tuupanen, S., et al. (2010). COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer. Br j cancer, Vol.102 (2), pp. 447-454. show abstract
It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT..
Crowther-Swanepoel, D., Corre, T., Lloyd, A., Gaidano, G., Olver, B., Bennett, F.L., Doughty, C., Toniolo, D., Caligaris-Cappio, F., Ghia, P., et al. (2010). Inherited genetic susceptibility to monoclonal B-cell lymphocytosis. Blood, Vol.116 (26), pp. 5957-5960. show abstract
Monoclonal B-cell lymphocytosis (MBL) is detectable in > 3% of the general population. Recent data are compatible, at least in a proportion of cases, with MBL being a progenitor lesion for chronic lymphocytic leukemia (CLL) and a surrogate for inherited predisposition. Common single nucleotide polymorphisms (SNPs) at 2q13 (rs17483466), 2q37.1 (rs13397985), 2q37.3 (rs757978), 6p25.3 (rs872071), 8q24.21 (rs2456449), 11q24.1 (rs735665), 15q21.3 (rs7169431), 15q23 (rs7176508), 16q24.1 (rs305061), and 19q13.32 (rs11083846) have been shown to confer a modest but significant increase in CLL risk. To examine the impact of these 10 SNPs on MBL, we analyzed 3 case-control series totaling 419 cases and 1753 controls. An association between genotype and MBL risk was seen for 9 SNPs, 6 of which were statistically significant: rs17483466 (odds ratio [OR] =1.27; P = .02), rs13397985 (OR = 1.40; P = 1.72 × 10(-3)), rs757978 (OR = 1.38; P = .02), rs872071 (OR = 1.27; P = 7.75 × 10(-3)), rs2456449 (OR = 1.31; P = 3.14 × 10(-3)), and rs735665 (OR = 1.63; P = 6.86 × 10(-6)). Collectively, these data provide support for genetic variation influencing CLL risk through predisposition to MBL..
Carvajal-Carmona, L.G., Churchman, M., Bonilla, C., Walther, A., Lefevre, J.H., Kerr, D., Dunlop, M., Houlston, R., Bodmer, W.F. & Tomlinson, I., et al. (2010). Comprehensive assessment of variation at the transforming growth factor beta type 1 receptor locus and colorectal cancer predisposition. Proceedings of the national academy of sciences of the united states of america, Vol.107 (17), pp. 7858-7862.
Landi, M., Chatterjee, N., Yu, K., Jacobs, K., Bergen, A., Goldin, L., Goldstein, A., Wang, Z., Burdette, L., Albanes, D., et al. (2009). A comprehensive genome-wide association study of lung cancer. Cancer research, Vol.69.
Pittman, A.M., Twiss, P., Broderick, P., Lubbe, S., Chandler, I., Penegar, S. & Houlston, R.S. (2009). The CDH1-160C>A polymorphism is a risk factor for colorectal cancer. Int j cancer, Vol.125 (7), pp. 1622-1625. show abstract
Part of the inherited susceptibility to colorectal cancer (CRC) is caused by the coinheritance of common low risk variants. E-cadherin (CDH1) has an established role in CRC; somatic inactivation of CDH1 is a common early event, and germline mutations can cause early-onset CRC. The -160C>A promoter variant (rs16260) of CDH1 has been reported to influence CDH1 transcription and thereby represents a strong candidate for a predisposition locus. To examine this proposition, we conducted a two-staged association study based on genotyping a total of 5,679 CRC cases and 5,412 controls for rs16260. CDH1-160C>A genotype was associated with CRC risk (p(trend) = 0.001). Compared to common homozygotes, the odds ratios (ORs) of CRC associated with heterozygous and homozygote variant genotype were 0.90 (95% confidence interval [CI]: 0.84-0.97) and 0.81 (95% CI: 0.71-0.93), respectively. In combination with the previously identified 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 risk variants, the risk of CRC increases with an increasing numbers of variant alleles for the 7 loci (OR(per allele) = 1.16; 95% CI: 1.13-1.19; p(trend) = 1.68 x 10(-34)). These data indicate CDH1-160C>A is a risk factor for CRC, and because a high proportion of the European population are carriers of at-risk genotypes, the variant is likely to contribute substantially to the development of CRC. Furthermore, our study underscores the importance of conducting association studies using large sample series to demonstrate polymorphic variants conferring modest relative risks..
Lubbe, S.J., Webb, E.L., Chandler, I.P. & Houlston, R.S. (2009). Implications of familial colorectal cancer risk profiles and microsatellite instability status. J clin oncol, Vol.27 (13), pp. 2238-2244. show abstract
PURPOSE: Estimating familial colorectal cancer (CRC) risk is clinically important in being able to discriminate between high- and low-risk groups. To quantify familial CRC risks associated with mismatch repair (MMR) deficient and microsatellite stable (MSS) tumors, we analyzed 2,941 population-based cases of CRC. PATIENTS AND METHODS: MMR status in CRCs was established by testing for microsatellite instability (MSI). MUTYH status was assigned by screening for Y165C and G382D variants. Age-specific relative and absolute CRC risks in first-degree relatives (FDRs) were calculated, and the most likely genetic models of familial aggregation were derived. RESULTS: CRC risks in FDRs were strongly associated with MSI status (MSI, standardized incidence ratio [SIR] = 4.28, 95% CI, 3.51 to 5.17; MSS, SIR = 1.91, 95% CI, 1.73 to 2.11), early-onset disease (MSI patient age < 55 years, SIR = 10.96, 95% CI, 8.32 to 14.17; MSS patient age < 55 years, SIR = 2.3, 95% CI, 1.88 to 2.85), and having more than one affected FDR (MSI, SIR = 10.00, 95% CI, 7.74 to 12.72; MSS, SIR = 2.78, 95% CI, 2.18 to 3.48). The familial aggregation of CRC associated with MSI cancer was parsimonious with dominant model conferring a high CRC risk at early ages. Approximately 69% of the excess familial risk in FDRs can be ascribed to MSS CRC, and although the pattern of familial risk supports recessive susceptibility in addition to MUTYH, the absolute risk of CRC is at best modest. CONCLUSION: The results from this analysis should enable an individual's risk of CRC to be more accurately estimated, thus maximizing the value of screening programs. Results also have utility in the design of genetic analyses to identify novel disease alleles..
Wijnen, J.T., Brohet, R.M., van Eijk, R., Jagmohan-Changur, S., Middeldorp, A., Tops, C.M., van Puijenbroek, M., Ausems, M.G., Gómez García, E., Hes, F.J., et al. (2009). Chromosome 8q23 3 and 11q23 1 variants modify colorectal cancer risk in Lynch syndrome. Gastroenterology, Vol.136 (1), pp. 131-137. show abstract
BACKGROUND & AIMS: Recent genome-wide association studies have identified common low-risk variants for colorectal cancer (CRC). To assess whether these influence CRC risk in the Lynch syndrome, we genotyped these variants in a large series of proven mutation carriers. METHODS: We studied 675 individuals from 127 different families from the Dutch Lynch syndrome Registry whose mutation carrier status was known. We genotyped 8q24.21, 8q23.3, 10p14, 11q23.1, 15q13.3, and 18q21.1 variants in carriers of a mismatch repair gene mutation. Univariate and multivariate analysis was used to analyse the association between the presence of a risk variant and CRC risk. RESULTS: A significant association was found between CRC risk and rs16892766 (8q23.3) and rs3802842 (11q23.1). For rs16892766, possession of the C-allele was associated with an elevated risk of CRC in a dose-dependent fashion, with homozygosity for CC being associated with a 2.16-fold increased risk. For rs3802842, the increased risk of CRC associated with the C-allele was only found among female carriers, while CRC risk was substantially higher among homozygous (hazard ratio [HR] 3.08) than among heterozygous carriers of the C-allele (HR 1.49). In an additive model of both variants, the risk was significantly associated with the number of risk alleles (HR 1.60 for carriers of 2 or more risk alleles). The effects were stronger in female carriers than in male carriers. CONCLUSION: We have identified 2 loci that are significantly associated with CRC risk in Lynch syndrome families. These modifiers may be helpful in identifying high-risk individuals who require more intensive surveillance..
Houlston, R. (2009). [Identification of low-penetrance alleles associated with colon cancer risk]. Med sci (paris), Vol.25 Spec No 1, pp. 39-41. show abstract
Colorectal cancer affects over 500,000 individuals yearly. Much of the benefit of colorectal cancer screening has been attributed to detection and removal of adenomatous polyps, highlighting the importance of colorectal polyps as targets for intervention and as biomarkers for colorectal cancer risk. Positive familial history (first or second degree relative) for colorectal carcinoma can be found in approximately 30% of all newly diagnosed cases, but less than 5% will be due to a defined genetic category of hereditary CRC. Genome-wide association studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer. The risks conferred by the susceptibility alleles are low. The combined effects may, however, be sufficiently large to be useful for risk prediction, and targeted screening and prevention, particularly as more loci are identified..
Crowther-Swanepoel, D. & Houlston, R.S. (2009). The molecular basis of familial chronic lymphocytic leukemia. Haematologica, Vol.94 (5), pp. 606-609. show abstract
Our understanding of the genetic basis of chronic lymphocytic leukemia is only just starting to be recognized. This perspective article by Drs. Crowther-Swanepoel and Houlston provides an up-to-date review the molecular epidemiology of chronic lymphocytic leukemia, with emphasis on the integration of biology and genomics..
Gibson, L., Johnson, N., Fraser, A., Silva, I.D., Houlston, R., Peto, J. & Fletcher, O. (2009). No Breast Cancer Association for Transforming Growth Factor-beta Pathway Colorectal Cancer Single Nucleotide Polymorphisms. Cancer epidem biomar, Vol.18 (6), pp. 1934-1936. show abstract
SMAD7 and GREM1 are signaling components on the transforming growth factor-beta pathway, which regulates normal mammary gland development and has been implicated in breast tumor invasion and metastasis. Three variants within SMAD7 and two variants in CRAC1 (a colorectal cancer-associated region on chromosome 15 in which GREM1 is located) have been associated with colorectal cancer risks [odds ratios (OR), 0.85-1.26; all P < 10(-7)]. We genotyped these five variants in a series of 1,267 bilateral breast cancer cases and 900 controls to determine whether they are associated with breast as well as colorectal cancer risk. None of these single nucleotide polymorphisms were associated with breast cancer risk in our study and the 95% confidence limits of our data, pooled with data from the Cancer Genetic Markers of Susceptibility study, exclude per allele ORs of <0.94 or >1.08. One or more of these variants may be associated with a very small OR for breast cancer, but our data suggest that the effects of these alleles are cancer site-specific. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1934-6).
Pittman, A.M., Naranjo, S., Webb, E., Broderick, P., Lips, E.H., van Wezel, T., Morreau, H., Sullivan, K., Fielding, S., Twiss, P., et al. (2009). The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression. Genome res, Vol.19 (6), pp. 987-993. show abstract
Recent genome-wide scans for colorectal cancer (CRC) have revealed the SMAD7 (mothers against decapentaplegic homolog 7) gene as a locus associated with a modest, but highly significant increase in CRC risk. To identify the causal basis of the association between 18q21 variation and CRC, we resequenced the 17-kb region of linkage disequilibrium and evaluated all variants in 2532 CRC cases and 2607 controls. A novel C to G single nucleotide polymorphism (SNP) at 44,703,563 bp was maximally associated with CRC risk (P = 5.98 x 10(-7); > or =1.5-fold more likely to be causal than other variants). Using transgenic assays in Xenopus laevis as a functional model, we demonstrate that the G risk allele leads to reduced reporter gene expression in the colorectum (P = 5.4 x 10(-3)). Electrophoretic mobility shift assays provided evidence for the role of Novel 1 in transcription factor binding. We propose that the novel SNP we have identified is the functional change leading to CRC predisposition through differential SMAD7 expression and, hence, aberrant TGF-beta signaling..
Zienolddiny, S., Skaug, V., Landvik, N.E., Ryberg, D., Phillips, D.H., Houlston, R. & Haugen, A. (2009). The TERT-CLPTM1L lung cancer susceptibility variant associates with higher DNA adduct formation in the lung. Carcinogenesis, Vol.30 (8), pp. 1368-1371. show abstract
Genome-wide association studies have provided evidence that common variation at 5p15.33 [telomerase reverse transcriptase (TERT)-cleft lip and palate transmembrane 1-like (CLPTM1L)], 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) influences lung cancer risk and cancer types with strong environmental risk factors. To independently validate these associations, we compared 5p15.33 (rs402710, rs401681), 6p21.33 (rs4324798) and 15q25.1 (rs1051730, rs16969968 and rs8034191) genotypes in 365 non-small cell lung cancer cases and 440 controls. Consistent with published data, variant genotypes of 5p15 (rs402710), 6p21 and 15q25 showed dose-dependent associations with lung cancer risk. To examine if variants influence the impact of environmental risk factors on lung carcinogenesis, we studied the relationship between genotype and levels of bulky aromatic/hydrophobic DNA adducts in lung tissue adjacent to tumor from 204 lung cancer cases. The risk allele of rs402710 (TERT-CLPTM1L locus) was associated with significantly higher levels of bulky aromatic/hydrophobic DNA adducts (P = 0.02). These data demonstrate a potential association between the TERT-CLPTM1L variant and levels of bulky DNA adducts measured by P-32-postlabeling and hence a basis for susceptibility to the development of lung cancer..
Shete, S., Hosking, F.J., Robertson, L.B., Dobbins, S.E., Sanson, M., Malmer, B., Simon, M., Marie, Y., Boisselier, B., Delattre, J.-., et al. (2009). Genome-wide association study identifies five susceptibility loci for glioma. Nat genet, Vol.41 (8), pp. 899-904. show abstract
To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 x 10(-17)), 8q24.21 (rs4295627, CCDC26; P = 2.34 x 10(-18)), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 x 10(-15)), 20q13.33 (rs6010620, RTEL1; P = 2.52 x 10(-12)) and 11q23.3 (rs498872, PHLDB1; P = 1.07 x 10(-8)). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor..
Tuupanen, S., Turunen, M., Lehtonen, R., Hallikas, O., Vanharanta, S., Kivioja, T., Björklund, M., Wei, G., Yan, J., Niittymäki, I., et al. (2009). The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nat genet, Vol.41 (8), pp. 885-890. show abstract
Homozygosity for the G allele of rs6983267 at 8q24 increases colorectal cancer (CRC) risk approximately 1.5 fold. We report here that the risk allele G shows copy number increase during CRC development. Our computer algorithm, Enhancer Element Locator (EEL), identified an enhancer element that contains rs6983267. The element drove expression of a reporter gene in a pattern that is consistent with regulation by the key CRC pathway Wnt. rs6983267 affects a binding site for the Wnt-regulated transcription factor TCF4, with the risk allele G showing stronger binding in vitro and in vivo. Genome-wide ChIP assay revealed the element as the strongest TCF4 binding site within 1 Mb of MYC. An unambiguous correlation between rs6983267 genotype and MYC expression was not detected, and additional work is required to scrutinize all possible targets of the enhancer. Our work provides evidence that the common CRC predisposition associated with 8q24 arises from enhanced responsiveness to Wnt signaling..
Di Bernardo, M.C., Matakidou, A., Eisen, T., Houlston, R.S. & GELCAPS Consortium, (2009). Plasminogen activator inhibitor variants PAI-1 A15T and PAI-2 S413C influence lung cancer prognosis. Lung cancer, Vol.65 (2), pp. 237-241. show abstract
The plasminogen pathway plays an important role in the behavior of many tumors including lung cancer. Hence genetic variants encoding plasminogen activator (PLAU), plasminogen receptor (PLAUR), plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) may contribute to lung cancer prognosis. To investigate this proposition we genotyped PAI-1 A15T, PLAU L141P, PLAUR L317P and PAI-2 S413C variants in 698 patients with lung cancer, 522 with non-small cell (NSCLC) and 176 with small cell lung cancer (SCLC). PAI-1 A15T was significantly associated with overall survival (OS), with carriers of variant alleles having a worse prognosis (hazard ratio (HR)=1.14; 95% confidence interval [CI]: 1.03-1.26). An association was also detected between OS in NSCLC and carrier status for PAI-2 413C (HR=1.13; 95% CI: 1.01-1.24). These common genetic variants identified warrant further evaluation as promising prognostic markers of patient outcome..
Song, H., Ramus, S.J., Tyrer, J., Bolton, K.L., Gentry-Maharaj, A., Wozniak, E., Anton-Culver, H., Chang-Claude, J., Cramer, D.W., DiCioccio, R., et al. (2009). A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22 2. Nat genet, Vol.41 (9), pp. 996-1000. show abstract
Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and approximately 2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10(-8)). The most significant SNP (rs3814113; P = 2.5 x 10(-17)) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79-0.86, P(trend) = 5.1 x 10(-19)). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77, 95% CI 0.73-0.81, P(trend) = 4.1 x 10(-21))..
Papaemmanuil, E., Hosking, F.J., Vijayakrishnan, J., Price, A., Olver, B., Sheridan, E., Kinsey, S.E., Lightfoot, T., Roman, E., Irving, J.A., et al. (2009). Loci on 7p12 2, 10q21 2 and 14q11 2 are associated with risk of childhood acute lymphoblastic leukemia. Nat genet, Vol.41 (9), pp. 1006-1010. show abstract
To identify risk variants for childhood acute lymphoblastic leukemia (ALL), we conducted a genome-wide association study of two case-control series, analyzing the genotypes with respect to 291,423 tagging SNPs in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601, odds ratio (OR) = 1.69, P = 1.20 x 10(-19)), 10q21.2 (ARID5B, rs7089424, OR = 1.65, P = 6.69 x 10(-19)) and 14q11.2 (CEBPE, rs2239633, OR = 1.34, P = 2.88 x 10(-7)). The 10q21.2 (ARID5B) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide new insight into disease causation of this specific hematological cancer. Notably, all three risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors..
Forsythe, E., Wild, R., Sellick, G., Houlston, R.S., Lehmann, A.R. & Wakeling, E. (2009). A novel DNA repair disorder with thrombocytopenia, nephrosis and features overlapping Cockayne syndrome. Am j med genet a, Vol.149A (10), pp. 2075-2079. show abstract
We report on four siblings with Cockayne-like syndrome with thrombocytopenia and nephrotic syndrome. The parents were healthy and consanguineous, consistent with an autosomal recessive mode of disease inheritance. UV irradiation of fibroblasts revealed an intermediate sensitivity between normal and standard Cockayne syndrome (CS) control cells. A genome-wide linkage scan conducted using Affymetrix 10K arrays provided exclusion of the known CS genes in the family, and evidence that the disease gene maps to 1p33-p31.1. Thrombocytopenia has not previously been linked with CS, but two patients with CS in association with nephrotic syndrome have previously been documented and the phenotypes are compared with the patients described here. We suggest that this Cockayne-like phenotype with thrombocytopenia and nephrotic syndrome may be a novel DNA repair disorder, and propose that further investigation of other affected families may help identify the causative genetic defect..
Middeldorp, A., Jagmohan-Changur, S., van Eijk, R., Tops, C., Devilee, P., Vasen, H.F., Hes, F.J., Houlston, R., Tomlinson, I., Houwing-Duistermaat, J.J., et al. (2009). Enrichment of Low Penetrance Susceptibility Loci in a Dutch Familial Colorectal Cancer Cohort. Cancer epidemiology biomarkers & prevention, Vol.18 (11), pp. 3062-3067.
Webb, E., Broderick, P., Lubbe, S., Chandler, I., Tomlinson, I. & Houlston, R.S. (2009). A genome-wide scan of 10 000 gene-centric variants and colorectal cancer risk. Eur j hum genet, Vol.17 (11), pp. 1507-1514. show abstract
Genome scans based on gene-centric single nucleotide polymorphisms (SNPs) have been proposed as an efficient approach to identify disease-causing variants that is complementary to scans based on tagging SNPs. Adopting this approach to identify low-penetrance susceptibility alleles for colorectal cancer (CRC) we analysed genotype data from 9109 gene-centric SNPs, 7014 of which were non-synonymous (nsSNPs), in 2873 cases and 2871 controls using Illumina iselect arrays. Overall the distribution of associations was not significantly different from the null. No SNP achieved globally significant association after correction for multiple testing (lowest P value 1.7 x 10(-4), rs727299). We then analysed the dataset incorporating information on the functional consequences of nsSNPs. We used results from the in silico algorithm PolyPhen as prior information to weight the association statistics, with weights estimated from the observed test statistics within predefined groups of SNPs. Incorporating this information did not, however, yield any further evidence of a specific association (lowest P value 2.2 x 10(-4), rs1133950). There was a strong relationship between effect size and SNPs predicted to be damaging (P=1.63 x 10(-5)), however, these variants which are most likely to impact on risk are rare (MAF<5%). Hence although the rationale for searching for low-penetrance cancer susceptibly alleles by conducting genome-wide scans of coding changes is strong, in practice it is likely that natural selection has rendered such alleles to be too rare to be detected by association studies of the size employed..
Landi, M.T., Chatterjee, N., Yu, K., Goldin, L.R., Goldstein, A.M., Rotunno, M., Mirabello, L., Jacobs, K., Wheeler, W., Yeager, M., et al. (2009). A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma. American journal of human genetics, Vol.85 (5), pp. 679-691.
Spain, S.L., Cazier, J.-., Houlston, R., Carvajal-Carmona, L., Tomlinson, I. & Consortium, C.O. (2009). Colorectal Cancer Risk Is Not Associated with Increased Levels of Homozygosity in a Population from the United Kingdom. Cancer research, Vol.69 (18), pp. 7422-7429.
Carvajal-Carmona, L.G., Spain, S., Kerr, D., Houlston, R., Cazier, J.-., Tomlinson, I. & Consortium, C.O. (2009). Common variation at the adiponectin locus is not associated with colorectal cancer risk in the UK. Human molecular genetics, Vol.18 (10), pp. 1889-1892.
Broderick, P., Wang, Y., Vijayakrishnan, J., Matakidou, A., Spitz, M.R., Eisen, T., Amos, C.I. & Houlston, R.S. (2009). Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study. Cancer res, Vol.69 (16), pp. 6633-6641. show abstract
To explore the impact of common variation on the risk of developing lung cancer, we conducted a two-phase genome-wide association (GWA) study. In phase 1, we compared the genotypes of 511,919 tagging single nucleotide polymorphisms (SNP) in 1,952 cases and 1,438 controls; in phase 2, 30,568 SNPs were genotyped in 2,465 cases and 3,005 controls. SNP selection was based on best supported P values from phase 1 and two other GWA studies of lung cancer. In the combined analysis of phases 1 and 2, the strongest associations identified were defined by SNPs mapping to 15q25.1 (rs12914385; P = 3.19 x 10(-16)), 5p15.33 (rs4975616; P = 6.66 x 10(-7)), and 6p21.33 (rs3117582; P = 9.13 x 10(-7)). Variation at 15q25.1, but not 5p15.33 or 6p21.33, was strongly associated with smoking behavior with risk alleles correlated to higher consumption. Variation at 5p15.33 was shown to significantly influence induction of lung cancer histology. Pooling data from the four series provided 21,620 genotypes for 7,560 cases and 8,205 controls. A meta-analysis provided increased support that variation at 15q25.1 (rs8034191; P = 3.24 x 10(-26)), 5p15.33 (rs4975616; P = 2.99 x 10(-9)), and 6p21.33 (rs3117582; P = 4.46 x 10(-10)) influences lung cancer risk. The next best-supported associations were attained at 15q15.2 (rs748404: P = 1.08 x 10(-6)) and 10q23.31 (rs1926203; P = 1.28 x 10(-6)). These data indicate few common variants account for 1% of the excess familial risk underscoring the necessity of having additional large sample series for gene discovery..
Bethke, L., Sullivan, K., Webb, E., Murray, A., Schoemaker, M., Auvinen, A., Kiuru, A., Salminen, T., Johansen, C., Christensen, H.C., et al. (2009). CASP8 D302H and meningioma risk: an analysis of five case-control series. Cancer lett, Vol.273 (2), pp. 312-315. show abstract
Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma..
Skoglund Lundin, J., Vandrovcova, J., Song, B., Zhou, X., Zelada-Hedman, M., Werelius, B., Houlston, R.S. & Lindblom, A. (2009). TGFBR1 variants TGFBR1(*)6A and Int7G24A are not associated with an increased familial colorectal cancer risk. Br j cancer, Vol.100 (10), pp. 1674-1679. show abstract
Variants of the transforming growth factor-beta receptor type 1 (TGFBR1) gene, TGFBR1*6A and Int7G24A, have been suggested to act as low-penetrance tumour susceptibility alleles with TGFBR1*6A being causally responsible for some cases of familial colorectal cancer (CRC). We performed a case-control study of 262 unrelated familial CRC cases; 83 hereditary non-polyposis colorectal cancer (HNPCC) and 179 non-HNPCC. Patients were genotyped for TGFBR1*6A and Int7G24A and compared with 856 controls. Further, we screened the coding region of TGFBR1 in affected members of a large family with CRC linked to 9q22.32-31.1. TGFBR1*6A allelic frequency was not significantly different in all of the familial cases compared with controls (0.107 and 0.106, respectively; P=0.915). In a subgroup analysis allele frequencies were, however, different between HNPCC and non-HNPCC familial cases (0.157 and 0.084, respectively; P=0.013). TGFBR1*6A genotype did not influence age of onset. Int7G24A allele frequencies were similar in cases and controls. No germ-line mutation was identified in the family with CRC linked to this chromosomal region. Our study provides no substantial support for the hypothesis that the polymorphic variants TGFBR1*6A or Int7G24A contribute to familial CRC risk. We cannot, however, exclude the possibility that TGFBR1 variants have a modifying effect on inherited risk per se..
Lubbe, S.J., Di Bernardo, M.C., Chandler, I.P. & Houlston, R.S. (2009). Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J clin oncol, Vol.27 (24), pp. 3975-3980. show abstract
PURPOSE: Biallelic mutations in the base excision DNA repair gene MUTYH predispose to colorectal cancer (CRC). Evidence that monoallelic mutations also confer an elevated CRC risk is controversial. Precise quantification of the CRC risk and the phenotype associated with MUTYH mutations is relevant to the counseling, surveillance, and clinical management of at-risk individuals. METHODS: We analyzed a population-based series of 9,268 patients with CRC and 5,064 controls for the Y179C and G396D MUTYH mutations. We related genotypes to phenotype and calculated genotype-specific CRC risks. RESULTS: Overall, biallelic mutation status conferred a 28-fold increase in CRC risk (95% CI,17.66 to 44.06); this accounted for 0.3% of CRCs in the cohort. Genotype relative risks of CRC were strongly age dependent, but penetrance was incomplete at age 60 years. CRC that developed in the context of biallelic mutations were microsatellite stable. Biallelic mutation carriers were more likely to have proximal CRC (P = 4.0 x 10(-4)) and synchronous polyps (P = 5.7 x 10(-9)) than noncarriers. The performance characteristics of clinicopathologic criteria for the identification of biallelic mutations are poor. Monoallelic mutation was not associated with an increased CRC risk (odds ratio, 1.07; 95% CI, 0.87 to 1.31). CONCLUSION: The high risk and the propensity for proximal disease associated with biallielic MUTYH mutation justify colonoscopic surveillance. Although mutation screening should be directed to patients with APC-negative polyposis and early-onset proximal MSS CRC in whom detection rates will be highest, the expanded phenotype associated with MUTYH mutation needs to be recognized. There is no evidence than monoallelic mutation status per se is clinically important..
Crowther-Swanepoel, D., Qureshi, M., Dyer, M.J., Matutes, E., Dearden, C., Catovsky, D. & Houlston, R.S. (2009). Genetic variation in CXCR4 and risk of chronic lymphocytic leukemia. Blood, Vol.114 (23), pp. 4843-4846. show abstract
A genome-wide linkage scan has provided evidence for a chronic lymphocytic leukemia (CLL) susceptibility locus at 2q21 to which the chemokine receptor CXCR4 gene maps. Recent data provide some evidence for common variation in CXCR4 according to the polymorphic variant rs2228014 defining CLL risk. To examine the role of genetic variation in CXCR4 on CLL risk, we screened 188 familial CLL cases and 213 controls for germline mutations in the coding regions of CXCR4 and genotyped rs2228014 in 1058 CLL cases and 1807 controls. No association between rs2228014 and risk of CLL was seen (P = .83). One truncating (W195X) and 2 missense mutations with possible functional consequences (V139I and G335S) were identified among 186 familial cases and 0 in 213 controls sequenced. Our analysis provides no evidence that common variation in CXCR4 defined by rs228014 influences the risk of CLL, but that functional coding mutations in CXCR4 may contribute to familial CLL..
Bibby, R.A., Tang, C., Faisal, A., Drosopoulos, K., Lubbe, S., Houlston, R., Bayliss, R. & Linardopoulos, S. (2009). A cancer-associated aurora A mutant is mislocalized and misregulated due to loss of interaction with TPX2. J biol chem, Vol.284 (48), pp. 33177-33184. show abstract
Mutations in protein kinases can drive cancer through alterations of the kinase activity or by uncoupling kinase activity from regulation. Changes to protein expression in Aurora A, a mitotic Ser/Thr kinase, are associated with the development of several human cancers, but the effects of somatic cancer-associated mutations have not been determined. In this study we show that Aurora A kinase activity is altered in different ways in three somatic cancer-associated mutations located within the catalytic domain; Aurora A(V174M) shows constitutively increased kinase activity, Aurora A(S155R) activity is decreased primarily due to misregulation, and Aurora A(S361*) activity is ablated due to loss of structural integrity. These alterations suggest vastly different mechanisms for the role of these three mutations in human cancer. We have further characterized the Aurora A(S155R) mutant protein, found that its reduced cellular activity and mislocalization are due to loss of interaction with TPX2, and deciphered the structural basis of the disruption at 2.5 A resolution. Previous studies have shown that disruption of the Aurora A/TPX2 interaction results in defective spindles that generate chromosomal abnormalities. In a panel of 40 samples from microsatellite instability-positive colon cancer patients, we found one example in which the tumor contained only Aurora A(S155R), whereas the normal tissue contained only wild-type Aurora A. We propose that the S155R mutation is an example of a somatic mutation associated with this tumor type, albeit at modest frequency, that could promote aneuploidy through the loss of regulated interactions between Aurora A and its protein partners..
Hubner, R.A. & Houlston, R.S. (2009). Folate and colorectal cancer prevention. Br j cancer, Vol.100 (2), pp. 233-239. show abstract
Anti-folate chemotherapy agents such as methotrexate and fluorouracil reduce proliferation of neoplastic cells by inhibiting DNA synthesis. Paradoxically epidemiological data suggests an inverse relationship between dietary folate intake and incidence of colorectal cancer (CRC). On the basis of this and other putative health benefits around 35% of the North American population take folic acid supplements, in addition to natural food folates and fortified flour and cereal grains. Recently, randomised controlled trials investigating folic acid as a secondary preventative agent in colorectal neoplasia have shed further light on the relationship between folate and colorectal carcinogenesis, corroborating data from animal models indicating opposing effects dependent on the timing of exposure in relation to the development of neoplastic foci. A 'dual-modulator' role for folate in colorectal carcinogenesis has been proposed in which moderate dietary increases initiated before the establishment of neoplastic foci have a protective influence, whereas excessive intake or increased intake once early lesions are established increases tumorigenesis. Functional polymorphic variants in genes encoding key enzymes in the folate metabolic pathway add a further layer of complexity to the relationship between folate and CRC risk. Here, we review the evidence concerning the efficacy and safety of folate as a potential CRC chemopreventive agent..
Forabosco, P., Neuhausen, S.L., Greco, L., Naluai, A.T., Wijmenga, C., Saavalainen, P., Houlston, R.S., Ciclitira, P.J., Babron, M.-. & Lewis, C.M., et al. (2009). Meta-analysis of genome-wide linkage studies in celiac disease. Hum hered, Vol.68 (4), pp. 223-230. show abstract
OBJECTIVE: A meta-analysis of genome-wide linkage studies allows us to summarize the extensive information available from family-based studies, as the field moves into genome-wide association studies. METHODS: Here we apply the genome scan meta-analysis (GSMA) method, a rank-based, model-free approach, to combine results across eight independent genome-wide linkages performed on celiac disease (CD), including 554 families with over 1,500 affected individuals. We also investigate the agreement between signals we identified from this meta-analysis of linkage studies and those identified from genome-wide association analysis using a hypergeometric distribution. RESULTS: Not surprisingly, the most significant result was obtained in the HLA region. Outside the HLA region, suggestive evidence for linkage was obtained at the telomeric region of chromosome 10 (10q26.12-qter; p = 0.00366), and on chromosome 8 (8q22.2-q24.21; p = 0.00491). Testing signals of association and linkage within bins showed no significant evidence for co-localization of results. CONCLUSION: This meta-analysis allowed us to pool the results from available genome-wide linkage studies and to identify novel regions potentially harboring predisposing genetic variation contributing to CD. This study also shows that linkage and association studies may identify different types of disease-predisposing variants..
Hubner, R.A., Muir, K.R., Liu, J.-., Logan, R.F., Grainge, M.J., Hulston, R.S. & Consortium, U.K. (2008). Dairy products, polymorphisms in the vitamin D receptor gene and colorectal adenoma recurrence. International journal of cancer, Vol.123 (3), pp. 586-593.
Sellick, G., Fielding, S., Qureshi, M., Catovsky, D., International Familial CLL Consortium, & Houlston, R. (2008). Germline mutations in RAD51, RAD51AP1, RAD51B, RAD51C,RAD51D, RAD52 and RAD54L do not contribute to familial chronic lymphocytic leukemia. Leuk lymphoma, Vol.49 (1), pp. 130-133. show abstract
While familial predisposition to B-cell chronic lymphocytic leukemia (CLL) is well recognized no gene which when mutated in the germline has been unambiguously shown to confer susceptibility to the disease. An approach based on mutation screening methods targeted to coding regions of candidate genes offers an attractive strategy for the identification of rare disease-causing alleles. The RAD genes participate in the cellular response to DNA double strand breaks, detecting DNA damage, activating cell cycle checkpoints and apoptosis. Defects in members of these genes are linked to increased chromosomal instability and in lymphoma predisposition, thereby representing strong candidate susceptibility genes a priori. To examine this proposition we screened 75 familial CLL probands for germline mutations in this set of genes. No overt pathogenic mutations were identified. These findings indicate that germline mutations in RAD51, RAD51AP1, RAD51L1, RAD51L3, RAD52 and RAD54L are unlikely to be causal of an inherited predisposition to CLL..
Jaeger, E., Webb, E., Howarth, K., Carvajal-Carmona, L., Rowan, A., Broderick, P., Walther, A., Spain, S., Pittman, A., Kemp, Z., et al. (2008). Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13 3 influence colorectal cancer risk. Nat genet, Vol.40 (1), pp. 26-28. show abstract
We mapped a high-penetrance gene (CRAC1; also known as HMPS) associated with colorectal cancer (CRC) in the Ashkenazi population to a 0.6-Mb region on chromosome 15 containing SCG5 (also known as SGNE1), GREM1 and FMN1. We hypothesized that the CRAC1 locus harbored low-penetrance variants that increased CRC risk in the general population. In a large series of colorectal cancer cases and controls, SNPs near GREM1 and SCG5 were strongly associated with increased CRC risk (for rs4779584, P=4.44x10(-14))..
Pittman, A.M., Webb, E., Carvajal-Carmona, L., Howarth, K., Di Bernardo, M.C., Broderick, P., Spain, S., Walther, A., Price, A., Sullivan, K., et al. (2008). Refinement of the basis and impact of common 11q23 1 variation to the risk of developing colorectal cancer. Hum mol genet, Vol.17 (23), pp. 3720-3727. show abstract
The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression..
Hubner, R.A., Muir, K.R., Liu, J.-., Logan, R.F., Grainge, M.J., Houlston, R.S. & Members of UKCAP Consortium, (2008). Dairy products, polymorphisms in the vitamin D receptor gene and colorectal adenoma recurrence. Int j cancer, Vol.123 (3), pp. 586-593. show abstract
Vitamin D receptor (VDR) activation inhibits proliferation and angiogenesis in the colorectal epithelium, and inhibits metastasis of colorectal tumors. Polymorphisms in the VDR gene alter receptor cellular levels and functioning, and may confer altered susceptibility to colorectal neoplasia. We aimed to investigate the influence of VDR polymorphisms and dietary factors impacting on vitamin D metabolism on colorectal adenoma (CRA) recurrence. Data on dietary intakes of calcium, vitamin D and dairy products were collected from 853 participants in the United Kingdom Colorectal Adenoma Prevention trial, a randomized trial of aspirin and folate for CRA recurrence prevention. The VDR Cdx2, FokI, BsmI, ApaI and TaqI polymorphisms were genotyped in 546 participants with available DNA, and gene-diet interaction analyses performed in 480. Dairy product intake was inversely related to CRA recurrence risk independent of calcium and vitamin D [relative risk (RR) = 0.64; 95% confidence intervals (CIs): 0.47-0.88, for subjects in the highest compared to lowest intake tertile, p(trend) = 0.005]. Milk accounted for 60% of dairy product intake, and on analysis of milk and nonmilk dairy products separately recurrence risk in individuals in the highest tertile of milk intake was half that of lowest tertile individuals (RR = 0.52; 95% CI: 0.38-0.72, p(trend) = 3.2 x 10(-5)), whereas nonmilk dairy products did not influence recurrence. VDR polymorphism genotypes and haplotypes did not directly alter recurrence risk, but the reduction in risk associated with high dairy product intake was confined to individuals with ApaI aA/AA genotype (p(interaction) = 0.02). These findings indicate dairy products, and in particular milk, have chemopreventive activity against CRA recurrence..
Sellick, G.S., Wade, R., Richards, S., Oscier, D.G., Catovsky, D. & Houlston, R.S. (2008). Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis. Blood, Vol.111 (3), pp. 1625-1633. show abstract
To identify genetic variants associated with outcome from chronic lymphocytic leukemia (CLL), we genotyped 977 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 755 genes with relevance to cancer biology in 425 patients participating in a phase 3 trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Selection of nsSNPs was biased toward those likely to be functionally deleterious. SNP genotypes were linked to individual patient outcome data and response to chemotherapy. The effect of genotype on progression-free survival (PFS) and overall survival (OS) was assessed by Cox regression analysis adjusting for treatment and clinico-pathologic variables. A total of 78 SNPs (51 dominantly acting and a further 27 recessively acting) were associated with PFS (9 also affecting OS) at the 5% level. These included SNPs mapping to the immune-regulation genes IL16 P434S (P = .03), IL19 S213F (P = .001), LILRA4 P27L (P = .004), KLRC4 S29I (P = .007), and CD5 V471A (P = .002); and DNA response genes POLB P242R (P = .04) and TOPBP1 S730L (P = .02), which were all independently prognostic of immunoglobulin heavy-chain variable region (IgV(H)) mutational status. The variants identified warrant further evaluation as promising prognostic markers of patient outcome. To facilitate the identification of prognostic markers through pooled analyses, we have made all data from our analysis publicly available..
Broderick, P., Sellick, G., Fielding, S., Catovsky, D. & Houlston, R. (2008). Lack of a relationship between the common 18q24 variant rs12953717 and risk of chronic lymphocytic leukemia. Leuk lymphoma, Vol.49 (2), pp. 271-272. show abstract
Linkage has implicated variation in 18q24 in genetic susceptibility to chronic lymphocytic leukemia (CLL). 18q24 harbors mothers against decapentaplegic homolog 7 (SMAD7), an intracellular antagonist of TGF-beta signaling which participates in a negative feedback loop controlling growth arrest and apoptosis of B-cells. Recently we have demonstrated variation in SMAD7, defined by the single nucleotide polymorphism rs12953717, to be strongly associated with risk of colorectal cancer. Given that many polymorphic variants have pleiotropic effects we explore the relationship between polymorphic variation at rs12953717 and CLL we compared the frequency of genotypes in 984 cases and 4831 healthy controls. There was therefore no evidence for an association between rs12953717 genotype and CLL; P = 0.40 (allelic test) with ORs of 0.99 (95% CI: 0.85 - 1.16) and 0.91 (95% CI: 0.74 - 1.11) for heterozygotes and TT homozygotes, respectively. These data suggests variation at SMAD7 does not significantly contribute to an inherited susceptibility to CLL..
Sellick, G.S., Broderick, P., Fielding, S., Catovsky, D. & Houlston, R.S. (2008). Lack of a relationship between the common 8q24 variant rs6983267 and risk of chronic lymphocytic leukemia. Leukemia, Vol.22 (2), pp. 438-439.
Fletcher, O., Johnson, N., Gibson, L., Coupland, B., Fraser, A., Leonard, A., Silva, I.D., Ashworth, A., Houlston, R. & Peto, J., et al. (2008). Association of genetic variants at 8q24 with breast cancer risk. Cancer epidem biomar, Vol.17 (3), pp. 702-705. show abstract
Recent whole genome association studies of prostate, breast, and colorectal cancer have identified susceptibility loci on 8q24. We genotyped three variants associated with prostate cancer (rs10090154, rs13254738, and rs7000448), one associated with both prostate and colorectal cancer (rs6983267), and one associated with breast cancer (rs13281615) in a series of 1,499 breast cancer cases and 1,390 controls. 1,267 (85%) of the cases had two primary breast cancers. Our analysis provides further evidence of the relationship between rs13281615 and risk of breast cancer, with heterozygote odds ratio (OR) 1.30 95% confidence interval (CI) 1.09-1.54 and homozygote OR 1.52 (95% CI, 1.22-1.89; P-trend = 0.00003), and confirms the prediction that the risk is substantially higher in this genetically enriched series (OR per allele, 1.24; 95% CI, 1.12-1.38) than in a large series of mainly unselected cases (reported OR per allele, 1.08; 95% CI, 1.05-1.11). We observed a protective effect of rs13254738 for breast cancer (allelic OR, 0.88; 95% CI, 0.78-0.98; P = 0.02), which is supported by the Cancer Genetic Markers of Susceptibility data (pooled allelic OR, 0.88; 95% CI, 0.81-0.96; P = 0.003). None of the other three single nucleotide polymorphisms, two associated with prostate (rs10090154 and rs7000448) and one with both prostate and colorectal cancers (rs6583267), was associated with breast cancer risk in our study. This evidence of a protective effect for breast cancer of one variant (rs13254738) that has been associated previously with a 1.25-fold increased risk of prostate cancer, with no effect for the two other variants, indicates that the effects of the risk alleles clustered at 8q24 are cancer site specific..
Chandler, I. & Houlston, R.S. (2008). Interobserver agreement in grading of colorectal cancers-findings from a nationwide web-based survey of histopathologists. Histopathology, Vol.52 (4), pp. 494-499. show abstract
AIMS: Tumour grade represents a gestalt of all molecular changes in malignancy, reflecting aggressiveness and has been shown to add prognostic information independent of stage for many malignancies, including colorectal cancer. Despite the grade of colorectal cancer being reported routinely in the UK, there is paucity of data on the level of agreement between histopathologists and hence the value of this metric in clinical practice. The aim was to estimate the degree of inter-observer variation in grading by conducting a nationwide web-based survey of histopathologists. METHODS AND RESULTS: Individuals were asked to grade a series of 20 tumours. Data from 104 pathologists surveyed indicates that agreement using both two and three grade systems is at best fair. CONCLUSION: Given that for the foreseeable future the histopathological criteria of stage and grade will still provide the mainstay of prognostication and therefore clinical decision-making, efforts should be made to improve grading criteria and standardize use of the low- and high-grade categories..
Bethke, L., Sullivan, K., Webb, E., Murray, A., Schoemaker, M., Auvinen, A., Kiuru, A., Salminen, T., Johansen, C., Christensen, H.C., et al. (2008). The common D302H variant of CASP8 is associated with risk of glioma. Cancer epidemiol biomarkers prev, Vol.17 (4), pp. 987-989. show abstract
Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and, hence, a defense against cancer. We tested the hypothesis that the CASP8 polymorphism D302H influences risk of glioma through analysis of five series of glioma case patients and controls (n = 1,005 and 1,011, respectively). Carrier status for the rare allele of D302H was associated with a 1.37-fold increased risk (95% confidence interval, 1.10-1.70; P = 0.004). The association of CASP8 D302H with glioma risk indicates the importance of inherited variation in the apoptosis pathway in susceptibility to this form of primary brain tumor..
Bethke, L., Webb, E., Murray, A., Schoemaker, M., Feychting, M., Lönn, S., Ahlbom, A., Malmer, B., Henriksson, R., Auvinen, A., et al. (2008). Functional polymorphisms in folate metabolism genes influence the risk of meningioma and glioma. Cancer epidemiol biomarkers prev, Vol.17 (5), pp. 1195-1202. show abstract
Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk..
Amos, C.I., Wu, X., Broderick, P., Gorlov, I.P., Gu, J., Eisen, T., Dong, Q., Zhang, Q., Gu, X., Vijayakrishnan, J., et al. (2008). Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25 1. Nat genet, Vol.40 (5), pp. 616-622. show abstract
To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 x 10(-17)) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk..
Tomlinson, I.P., Webb, E., Carvajal-Carmona, L., Broderick, P., Howarth, K., Pittman, A.M., Spain, S., Lubbe, S., Walther, A., Sullivan, K., et al. (2008). A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23 3. Nat genet, Vol.40 (5), pp. 623-630. show abstract
To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition..
Tenesa, A., Farrington, S.M., Prendergast, J.G., Porteous, M.E., Walker, M., Haq, N., Barnetson, R.A., Theodoratou, E., Cetnarskyj, R., Cartwright, N., et al. (2008). Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat genet, Vol.40 (5), pp. 631-637. show abstract
In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 x 10(-10)), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 x 10(-26)) and 18q21 (rs4939827; OR = 1.2; P = 7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology..
Geary, J., Sasieni, P., Houlston, R., Izatt, L., Eeles, R., Payne, S.J., Fisher, S. & Hodgson, S.V. (2008). Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). Fam cancer, Vol.7 (2), pp. 163-172. show abstract
The family histories of 130 individuals with documented hereditary non-polyposis colorectal cancer (HNPCC) (caused by mutations in mismatch-repair (MMR) genes MSH2 (n = 64), MLH1 (n = 62) or MSH6 (n = 4)) were obtained, and incidence of cancers in those families was compared to that in the general population. There were a total of 982 cancers in 723 individuals. Colorectal cancer (CRC) was the commonest type (64% and 55% in individuals from families with germline MLH1 and MSH2 mutations respectively). Median age at diagnosis of first CRC in MSH6 mutation families was 59 years compared to 45 years in both MLH1 and MSH2 mutation families. The relative risk (RR) of endometrial cancer was 55 in MSH2 mutation families, compared with 27 in MLH1 mutation families, and 37 in MSH6 mutation families; median age at diagnosis 49 years. Even within MSH2 families, endometrial cancer tended to cluster, with 28 of the 58 cases coming from families with three or more cases (P < 0.001). Absolute risk of endometrial cancer in MLH1 families was still greater than any other cancer (other than CRC). 5% of cancers in both MLH1 and MSH2 mutation families were gastric (RR = 12); 53% of these were diagnosed before 50 years. Seven cases of small intestinal cancer occurred in MSH2 and MLH1 mutation families (RR = 26). There were 13 cases of cancer of the ureter; all were in MSH2 families. These cancers tended to cluster within families (P < 0.001); three of seven families with urothelial cancer had such cases in two or more individuals; two others had kidney cancer. Nineteen of 27 ovarian cancers (70%) were in MSH2 mutation families and 70% of these were diagnosed before age 50 years. There were 9 cases of sebaceous skin cancer, 3 in two MLH1 and 6 in four MSH2 mutation families. Of 22 pancreatic cancers, 14 were known to be diagnosed before 60 years. Breast cancer RR was 1.7 overall. The type of mutation (truncating or other type, and site of mutation) showed no obvious correlation with the presence or absence of extra-colonic cancers in families..
Fuller, S.J., Papaemmanuil, E., McKinnon, L., Webb, E., Sellick, G.S., Dao-Ung, L.-., Skarratt, K.K., Crowther, D., Houlston, R.S. & Wiley, J.S., et al. (2008). Analysis of a large multi-generational family provides insight into the genetics of chronic lymphocytic leukemia. Br j haematol, Vol.142 (2), pp. 238-245. show abstract
We report the genetic analysis of a large multi-generational family composed of 144 individuals in which 11 members have been diagnosed with chronic lymphocytic leukaemia (CLL). The observation of a significant over-representation of monoclonal B-cell lymphocytosis (MBL) in unaffected family members strongly supports MBL being a surrogate marker of carrier status. A genome-wide linkage scan of the family using high-density 10K single nucleotide polymorphisms provided no significant evidence for a single gene model of disease susceptibility, inviting speculation that susceptibility to CLL has a more complex basis. The absence of a correlation in IGHV usage between affected family members does however argue strongly against exposure to a single super-antigen in disease development..
Walther, A., Houlston, R. & Tomlinson, I. (2008). Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis. Gut, Vol.57 (7), pp. 941-950.
Alhopuro, P., Phichith, D., Tuupanen, S., Sammalkorpi, H., Nybondas, M., Saharinen, J., Robinson, J.P., Yang, Z., Chen, L.-., Orntoft, T., et al. (2008). Unregulated smooth-muscle myosin in human intestinal neoplasia. Proc natl acad sci u s a, Vol.105 (14), pp. 5513-5518. show abstract
A recent study described a recessive ATPase activating germ-line mutation in smooth-muscle myosin (smmhc/myh11) underlying the zebrafish meltdown (mlt) phenotype. The mlt zebrafish develops intestinal abnormalities reminiscent of human Peutz-Jeghers syndrome (PJS) and juvenile polyposis (JP). To examine the role of MYH11 in human intestinal neoplasia, we searched for MYH11 mutations in patients with colorectal cancer (CRC), PJS and JP. We found somatic protein-elongating frameshift mutations in 55% of CRCs displaying microsatellite instability and in the germ-line of one individual with PJS. Additionally, two somatic missense mutations were found in one microsatellite stable CRC. These two missense mutations, R501L and K1044N, and the frameshift mutations were functionally evaluated. All mutations resulted in unregulated molecules displaying constitutive motor activity, similar to the mutant myosin underlying mlt. Thus, MYH11 mutations appear to contribute also to human intestinal neoplasia. Unregulated MYH11 may affect the cellular energy balance or disturb cell lineage decisions in tumor progenitor cells. These data challenge our view on MYH11 as a passive differentiation marker functioning in muscle contraction and add to our understanding of intestinal neoplasia..
Dallosso, A.R., Dolwani, S., Jones, N., Jones, S., Colley, J., Maynard, J., Idziaszczyk, S., Humphreys, V., Arnold, J., Donaldson, A., et al. (2008). Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3. Gut, Vol.57 (9), pp. 1252-1255. show abstract
BACKGROUND: MUTYH-associated polyposis (MAP) is a recessive trait characterised by multiple colorectal adenomas and a high risk of colorectal cancer. MUTYH functions in the DNA base excision repair pathway and has a key role in the repair of oxidative DNA damage. OBJECTIVES: To assess the contribution of inherited variants in genes involved in base excision repair and oxidative DNA damage including MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 to the multiple colorectal adenoma phenotype. METHODS: Inherited variants of MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 were sought in 167 unrelated patients with multiple colorectal adenomas whose family histories were consistent with recessive inheritance. These variants were also characterised in approximately 300 population controls. RESULTS: Thirty-three patients (20%) and no controls were MUTYH homozygotes or compound heterozygotes (ie, carried two mutations) and therefore had MAP. Eight different pathogenic MUTYH mutations were identified, of which four were novel. MAP cases had significantly more adenomas than non-MAP cases (p = 0.0009; exact test for trends in proportions) and presented earlier (p = 0.013; analysis of variance). Twenty-four protein-altering variants were identified upon screening of OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1. However, all combinations of two (or more) variants that were identified at an individual locus in patients were also seen in controls, and no variants were significantly over-represented (or under-represented) in cases. CONCLUSION: Multiple rare alleles of MUTYH are associated with autosomal recessive MAP, while OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 do not contribute significantly to autosomal recessive polyposis..
Chandler, I.P. & Houlston, R.S. (2008). Interobserver agreement in grading of colorectal cancers - findings from a nationwide web-based survey of histopathologists. Histopathology, Vol.53 (4), pp. 480-481.
Houlston, R.S. & Catovsky, D. (2008). Familial chronic lymphocytic leukemia. Curr hematol malig rep, Vol.3 (4), pp. 221-225. show abstract
The role of inherited genetic factors in the etiology of chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders is now well established. Significant familial aggregation of CLL and B-cell lymphoproliferative disorders has been demonstrated, but the mode of inheritance is unknown. Identification of genes that when mutated confer an increased risk of these diseases is of immediate clinical relevance because it may offer clues to pathogenesis and highlight possible therapeutic targets. Furthermore, identification of these genes provides a greater understanding of the mechanisms of B-cell tumorigenesis in general. This article reviews current knowledge relating to inherited susceptibility to CLL and strategies that are being used to identify disease-causing mutations..
Di Bernardo, M.C., Crowther-Swanepoel, D., Broderick, P., Webb, E., Sellick, G., Wild, R., Sullivan, K., Vijayakrishnan, J., Wang, Y., Pittman, A.M., et al. (2008). A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat genet, Vol.40 (10), pp. 1204-1210. show abstract
We conducted a genome-wide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia (CLL) and performed validation in two additional series totaling 1,529 cases and 3,115 controls. We identified six previously unreported CLL risk loci at 2q13 (rs17483466; P = 2.36 x 10(-10)), 2q37.1 (rs13397985, SP140; P = 5.40 x 10(-10)), 6p25.3 (rs872071, IRF4; P = 1.91 x 10(-20)), 11q24.1 (rs735665; P = 3.78 x 10(-12)), 15q23 (rs7176508; P = 4.54 x 10(-12)) and 19q13.32 (rs11083846, PRKD2; P = 3.96 x 10(-9)). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL..
Hung, R.J., Christiani, D.C., Risch, A., Popanda, O., Haugen, A., Zienolddiny, S., Benhamou, S., Bouchardy, C., Lan, Q., Spitz, M.R., et al. (2008). International Lung Cancer Consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways. Cancer epidemiol biomarkers prev, Vol.17 (11), pp. 3081-3089. show abstract
BACKGROUND: The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. METHODS: Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. RESULTS: Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. DISCUSSION: In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies..
COGENT Study, , Houlston, R.S., Webb, E., Broderick, P., Pittman, A.M., Di Bernardo, M.C., Lubbe, S., Chandler, I., Vijayakrishnan, J., Sullivan, K., et al. (2008). Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat genet, Vol.40 (12), pp. 1426-1435. show abstract
Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 x 10(-10)), 16q22.1 (rs9929218, CDH1; P = 1.2 x 10(-8)), 19q13.1 (rs10411210, RHPN2; P = 4.6 x 10(-9)) and 20p12.3 (rs961253; P = 2.0 x 10(-10)). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC..
Wang, Y., Broderick, P., Webb, E., Wu, X., Vijayakrishnan, J., Matakidou, A., Qureshi, M., Dong, Q., Gu, X., Chen, W.V., et al. (2008). Common 5p15 33 and 6p21 33 variants influence lung cancer risk. Nat genet, Vol.40 (12), pp. 1407-1409. show abstract
We conducted a genome-wide association (GWA) study of lung cancer comparing 511,919 SNP genotypes in 1,952 cases and 1,438 controls. The most significant association was attained at 15q25.1 (rs8042374; P = 7.75 x 10(-12)), confirming recent observations. Pooling data with two other GWA studies (5,095 cases, 5,200 controls) and with replication in an additional 2,484 cases and 3,036 controls, we identified two newly associated risk loci mapping to 6p21.33 (rs3117582, BAT3-MSH5; P(combined) = 4.97 x 10(-10)) and 5p15.33 (rs401681, CLPTM1L; P(combined) = 7.90 x 10(-9))..
Papaemmanuil, E., Carvajal-Carmona, L., Sellick, G.S., Kemp, Z., Webb, E., Spain, S., Sullivan, K., Barclay, E., Lubbe, S., Jaeger, E., et al. (2008). Deciphering the genetics of hereditary non-syndromic colorectal cancer. Eur j hum genet, Vol.16 (12), pp. 1477-1486. show abstract
Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P=0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=2.79; P=0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P=0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL=0.95, P=0.23; HLOD(dominant)=0.40, HLOD(recessive)=0.20). Our findings are consistent with the hypothesis that variation at 3q22 contributes to the risk of CRC, but this is unlikely to be mediated through a restricted set of alleles..
Bethke, L., Webb, E., Murray, A., Schoemaker, M., Johansen, C., Christensen, H.C., Muir, K., McKinney, P., Hepworth, S., Dimitropoulou, P., et al. (2008). Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma. Hum mol genet, Vol.17 (6), pp. 800-805. show abstract
Much of the variation in inherited risk of glioma is likely to be explained by combinations of common low risk variants. The established relationship between glioma risk and exposure to ionizing radiation led us to examine whether variants in the DNA repair genes contribute to disease susceptibility. We evaluated 1127 haplotype-tagging single-nucleotide polymorphisms (SNPs) supplemented with 388 putative functional SNPs to capture most of the common variation in 136 DNA repair genes, in five unique case-control series from four different countries (1013 cases, 1016 controls). We identified 16 SNPs associated with glioma risk at the 1% significance level. The highest association observed across the five independent case-control datasets involved rs243356, which maps to intron 3 of CHAF1A (trend odds ratio, 1.32; 95% confidence interval 1.14-1.54; P = 0.0002; false-positive report probability = 0.055, based on a prior probability of 0.01). Our results provide additional support for the hypothesis that low penetrance variants contribute to the risk of developing glioma and suggest that a genetic variant located in or around the CHAF1A gene contributes to disease risk..
Crowther-Swanepoel, D., Wild, R., Sellick, G., Dyer, M.J., Mauro, F.R., Cuthbert, R.J., Jonsson, V., Matutes, E., Dearden, C., Wiley, J., et al. (2008). Insight into the pathogenesis of chronic lymphocytic leukemia (CLL) through analysis of IgVH gene usage and mutation status in familial CLL. Blood, Vol.111 (12), pp. 5691-5693. show abstract
To address the proposition that familial B-cell chronic lymphocytic leukemia (CLL) may exhibit a more restricted phenotype than sporadic CLL with respect to immunoglobulin gene usage or ontogenic development, we compared immunoglobulin (Ig) heavy chain variable region (VH) gene usage and IgVH mutation status in 327 patients with CLL from 214 families with 724 patients with sporadic cases. The frequency of mutated CLL was higher in familial CLL (P < .001), and there was evidence of intrafamilial concordance in mutation status (P < .001). The repertoire and frequency of IgVH usage was, however, not significantly different between familial and sporadic CLL. Furthermore, IgVH usage was not correlated between affected members of the same family. These observations provide evidence that familial CLL is essentially indistinguishable from sporadic CLL, favoring a genetic basis to disease development in general rather than a simple environmental etiology..
Hubner, R.A., Muir, K.R., Liu, J.-., Logan, R.F., Grainge, M.J., Houlston, R.S. & Members of the UKCAP Consortium, (2008). Ornithine decarboxylase G316A genotype is prognostic for colorectal adenoma recurrence and predicts efficacy of aspirin chemoprevention. Clin cancer res, Vol.14 (8), pp. 2303-2309. show abstract
PURPOSE: The chemopreventive activity of aspirin in colorectal neoplasia may be explained in part by its effect on polyamine metabolism. The ornithine decarboxylase (ODC) G316A polymorphism affects polyamine metabolism through altered expression of ODC. We investigated the influence of ODC G316A on the chemopreventive activity of aspirin in colorectal adenoma (CRA) recurrence. EXPERIMENTAL DESIGN: We genotyped ODC G316A in 546 individuals in the United Kingdom Colorectal Adenoma Prevention trial of aspirin for CRA recurrence prevention and pooled our findings with data from two other randomized intervention trials. RESULTS: The United Kingdom Colorectal Adenoma Prevention participants with homozygous ODC 316AA genotype were at reduced CRA recurrence risk [relative risk (RR), 0.43; 95% confidence interval (95% CI), 0.16-1.15], particularly if also exposed to aspirin (RR, 0.24; 95% CI, 0.03-1.71). In the pooled analysis of 2,207 individuals, those with homozygous ODC 316AA genotype were at significantly reduced CRA recurrence risk (RR, 0.68; 95% CI, 0.47-0.99). Following stratification by genotype and aspirin exposure, individuals with homozygous wild-type or heterozygous genotypes derived modest benefit from aspirin (RR, 0.85; 95% CI, 0.72-1.01), whereas in those with both ODC 316AA genotype and aspirin exposure recurrence risk was halved (RR, 0.52; 95% CI, 0.29-0.91). CONCLUSION: The ODC G316A genotype is prognostic for CRA recurrence and predictive of an enhanced response to aspirin in preventing recurrence. This variant has the potential to be a clinically useful genetic marker to identify individuals likely to derive the greatest benefit from aspirin chemoprevention..
Allan, J.M., Sunter, N., Hall, A., Mainou-Fowler, T., Jackson, G., Summerfield, G., Harris, R.J., Pettitt, A., Houlston, R., Bailey, J., et al. (2008). A Common Genetic Variant in the 3'UTR of IRF4/MUM1 Associates with Risk of Disease and Poor Prognosis in Chronic Lymphocytic Leukaemia. Blood, Vol.112 (11), pp. 388-388.
Webb, E., Broderick, P., Chandler, I., Lubbe, S., Penegar, S., Tomlinson, I.P. & Houlston, R.S. (2008). Comprehensive analysis of common mitochondrial DNA variants and colorectal cancer risk. Br j cancer, Vol.99 (12), pp. 2088-2093. show abstract
Several lines of evidence implicate mitochondrial dysfunction in the development of cancer. To test the hypothesis that common mtDNA variation influences the risk of colorectal cancer (CRC), we genotyped 132 tagging mtDNA variants in a sample of 2854 CRC cases and 2822 controls. The variants examined capture approximately 80% of mtDNA common variation (excluding the hypervariable D-loop). We first tested for single marker associations; the strongest association detected was with A5657G (P=0.06). Overall the distribution of association P-values was consistent with a null distribution. Next, we classified individuals into the nine common European haplogroups and compared their distribution in cases and controls. This analysis also provided no evidence of an association between mitochondrial variation and CRC risk. In conclusion, our results provide little evidence that mitochondrial genetic background plays a role in modifying an individual's risk of developing CRC..
Liu, P., Vikis, H.G., Wang, D., Lu, Y., Wang, Y., Schwartz, A.G., Pinney, S.M., Yang, P., de Andrade, M., Petersen, G.M., et al. (2008). Familial aggregation of common sequence variants on 15q24-25 1 in lung cancer. J natl cancer inst, Vol.100 (18), pp. 1326-1330. show abstract
Three recent genome-wide association studies identified associations between markers in the chromosomal region 15q24-25.1 and the risk of lung cancer. We conducted a genome-wide association analysis to investigate associations between single-nucleotide polymorphisms (SNPs) and the risk of lung cancer, in which we used blood DNA from 194 case patients with familial lung cancer and 219 cancer-free control subjects. We identified associations between common sequence variants at 15q24-25.1 (that spanned LOC123688 [a hypothetical gene], PSMA4, CHRNA3, CHRNA5, and CHRNB4) and lung cancer. The risk of lung cancer was more than fivefold higher among those subjects who had both a family history of lung cancer and two copies of high-risk alleles rs8034191 (odds ratio [OR] = 7.20, 95% confidence interval [CI] = 2.21 to 23.37) or rs1051730 (OR = 5.67, CI = 2.21 to 14.60, both of which were located in the 15q24-25.1 locus, than among control subjects. Thus, further research to elucidate causal variants in the 15q24-25.1 locus that are associated with lung cancer is warranted..
Frank, B., Burwinkel, B., Bermejo, J.L., Foersti, A., Hemminki, K., Houlston, R., Mangold, E., Rahner, N., Friedl, W., Friedrichs, N., et al. (2008). Ten recently identified associations between nsSNPs and colorectal cancer could not be replicated in German families. Cancer letters, Vol.271 (1), pp. 153-157.
Frank, B., Wiestler, M., Kropp, S., Hemminki, K., Spurdle, A.B., Sutter, C., Wappenschmidt, B., Chen, X.Q., Beesley, J., Hopper, J.L., et al. (2008). Association of a common AKAP9 variant with breast cancer risk: A collaborative analysis. J natl cancer i, Vol.100 (6), pp. 437-442. show abstract
Data from several studies have suggested that polymorphisms in A-kinase anchoring proteins (AKAPs), which are key components of signal transduction, contribute to carcinogenesis. To evaluate the impact of AKAP variants on breast cancer risk, we genotyped six nonsynonymous sing le-nucleotide polymorphisms that were predicted to be deleterious and found two (M4631, 1389G>T and N2792S, 8375A>G) to be associated with an allele dose-dependent increase in risk of familial breast cancer in a German population. We extended the analysis of AKAP9 M4631, which is in strong linkage disequilibrium with AKAP9 N2792S, to 9523 breast cancer patients and 13770 healthy control subjects from seven independent European and Australian breast cancer studies. All statistical tests were two-sided. The collaborative analysis confirmed the association of M4631 with increased breast cancer risk. Among all breast cancer patients, the combined adjusted odds ratio (OR) of breast cancer for individuals homozygous for the rare allele TT (frequency = 0.19) compared with GG homozygotes was 1.17 (95% confidence interval [CL] = 1.08 to 1.27, P =.0003), and the OR for TT homozygotes plus GT heterozygotes compared with GG homozygotes was 1.10 (95% Cl = 1.04 to 1.17, P=.001). Among the combined subset of 2795 familial breast cancer patients, the respective ORs were 1.27 (95% Cl = 1.12 to 1.45, P =.0003) and 1.16 (95% Cl = 1.06 to 1.27, P =.001)..
Eisen, T., Matakidou, A., Houlston, R. & GELCAPS Consortium, (2008). Identification of low penetrance alleles for lung cancer: the GEnetic Lung CAncer Predisposition Study (GELCAPS). Bmc cancer, Vol.8, p. 244. show abstract
BACKGROUND: Part of the inherited risk to lung cancer is likely to include common, low risk alleles. The identification of this class of susceptibility is contingent on association-based analyses. We established GEnetic Lung CAncer Predisposition Study (GELCAPS) to collect DNA and clinico-pathological data from a large series of cases and a series of spouse/partner controls, thereby generating a key resource for the identification of low risk alleles. METHODS: GELCAPS was one of the first genetic epidemiological trials in the UK to be adopted by the National Cancer Research Network (NCRN) onto its portfolio with the participation of over 100 oncology departments specialising in the management of lung cancer. RESULTS: Samples from over 5,000 independent lung cancer cases and 2,000 controls have so far been assembled through GELCAPS. CONCLUSION: GELCAPS represents one of the largest datasets of its type in the world capable of informing on the contribution of low penetrance alleles to the development of lung cancer and the influence of genetic variation on outcome. In addition our experience in developing the GELCAPS serves to illustrate how large DNA biobanks for genetic analyses can be rapidly generated within the UK using the NCRN..
Bethke, L., Murray, A., Webb, E., Schoemaker, M., Muir, K., McKinney, P., Hepworth, S., Dimitropoulou, P., Lophatananon, A., Feychting, M., et al. (2008). Comprehensive analysis of DNA repair gene variants and risk of meningioma. J natl cancer inst, Vol.100 (4), pp. 270-276. show abstract
BACKGROUND: Meningiomas account for up to 37% of all primary brain tumors. Genetic susceptibility to meningioma is well established, with the risk among relatives of meningioma patients being approximately threefold higher than that in the general population. A relationship between risk of meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility. METHODS: We analyzed 1127 tagging single-nucleotide polymorphisms (SNPs) that were selected to capture most of the common variation in 136 DNA repair genes in five case-control series (631 case patients and 637 control subjects) from four countries in Europe. We also analyzed 388 putative functional SNPs in these genes for their association with meningioma. All statistical tests were two-sided. RESULTS: The SNP rs4968451, which maps to intron 4 of the gene that encodes breast cancer susceptibility gene 1-interacting protein 1, was consistently associated with an increased risk of developing meningioma. Across the five studies, the association was highly statistically significant (trend odds ratio = 1.57, 95% confidence interval = 1.28 to 1.93; P(trend) = 8.95 x 10(-6); P = .009 after adjusting for multiple testing). CONCLUSIONS: We have identified a novel association between rs4968451 and meningioma risk. Because approximately 28% of the European population are carriers of at-risk genotypes for rs4968451, the variant is likely to make a substantial contribution to the development of meningioma..
Pittman, A.M., Broderick, P., Sullivan, K., Fielding, S., Webb, E., Penegar, S., Tomlinson, I. & Houlston, R.S. (2008). CASP8 variants D302H and -652 6N ins/del do not influence the risk of colorectal cancer in the United Kingdom population. Br j cancer, Vol.98 (8), pp. 1434-1436. show abstract
Polymorphisms in CASP8 at 2q33.1 have been associated with the risk of developing cancer, specifically, the D302H variant (rs1045485) with breast cancer in the European population and the -652 6N ins/del promoter variant (rs3834129) with multiple tumours including colorectal cancer (CRC) in the Chinese population. We evaluated the relationship between -652 6N ins/del and D302H variants and risk of developing CRC in the UK population by genotyping 4016 cases and 3749 controls. Both variants showed no evidence of an association with risk of developing CRC (P=0.42 and 0.22, respectively). In contrast, the recently identified CRC susceptibility allele rs6983267 mapping to 8q24 was significantly associated with disease risk (P=8.94 x 10(-8)). It is thus very unlikely that variation in CASP8 defined by -652 6N ins/del or D302H influences the risk of CRC in European populations. The implications of our findings both in terms of population-specific effects and publication bias are discussed..
Aaltonen, L., Johns, L., Jaervinen, H., Mecklin, J.-. & Houlston, R. (2007). Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors. Clinical cancer research, Vol.13 (1), pp. 356-361.
Johnson, N., Fletcher, O., Palles, C., Rudd, M., Webb, E., Sellick, G., dos Santos Silva, I., McCormack, V., Gibson, L., Fraser, A., et al. (2007). Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility. Hum mol genet, Vol.16 (9), pp. 1051-1057. show abstract
Rare inactivating mutations in BRCA1, BRCA2, ATM, TP53 and CHEK2 confer relative risks for breast cancer between about 2 and more than 10, but more common variants in these genes are generally considered of little or no clinical significance. Under the polygenic model for breast cancer carriers of multiple low-penetrance alleles are at high risk, but few such alleles have been reliably identified. We analysed 1037 potentially functional single nucleotide polymorphisms (SNPs) in candidate cancer genes in 473 women with two primary breast cancers and 2463 controls. Twenty-five of these SNPs were in BRCA1, BRCA2, ATM, TP53 and CHEK2. Among the 1037 SNPs there were a few significant findings, but hardly more than would be expected in this large experiment. There was, however, a significant trend in risk with increasing numbers of variant alleles for the 25 SNPs in BRCA1, BRCA2, ATM, TP53 and CHEK2 (P(trend) = 0.005). For the 21 of these with minor allele frequency <10% this trend was highly significant (P(trend) = 0.00004, odds ratio for 3 or more SNPs = 2.90, 95% CI 1.69-4.97). The individual effects of most of these risk alleles were undetectably small even in this well powered study, but the risk conferred by multiple variants is readily detectable and makes a substantial contribution to susceptibility. A risk score incorporating a suitably weighted sum of all potentially functional variants in these and a few other candidate genes may provide clinically useful identification of women at high genetic risk..
Matakidou, A., el Galta, R., Webb, E.L., Rudd, M.F., Bridle, H., GELCAPS Consortium, , Eisen, T. & Houlston, R.S. (2007). Genetic variation in the DNA repair genes is predictive of outcome in lung cancer. Hum mol genet, Vol.16 (19), pp. 2333-2340. show abstract
To assess whether DNA repair gene variants influence the clinical behaviour of lung cancer we examined the impact of a comprehensive panel of 109 non-synonymous single-nucleotide polymorphisms (nsSNPs) in 50 DNA repair genes on overall survival (OS) in 700 lung cancer patients. Fifteen nsSNPs were associated with OS, significantly greater than that expected (P = 0.04). SNPs associated with prognosis mapped primarily to two repair pathways--nucleotide excision repair (NER): ERCC5 D1104H (P = 0.004); ERCC6 G399D (P = 0.023), ERCC6 Q1413R (P = 0.025), POLE (P = 0.014) and base excision repair: APEX1 D148E (P = 0.028); EXO1 E670G (P = 0.007); POLB P242R (P = 0.018). An increasing number of variant alleles in EXO1 was associated with a poorer prognosis [hazard ratio (HR) = 1.24; P = 0.0009]. A role for variation in NER and BRCA2/FA pathway genes as determinants of OS was provided by an analysis restricted to the 456 patients treated with platinum-based agents. Our data indicate that the pathway-based approach has the potential to generate prognostic markers of clinical outcome..
Sellick, G.S., Goldin, L.R., Wild, R.W., Slager, S.L., Ressenti, L., Strom, S.S., Dyer, M.J., Mauro, F.R., Marti, G.E., Fuller, S., et al. (2007). A high-density SNP genome-wide linkage search of 206 families identifies susceptibility loci for chronic lymphocytic leukemia. Blood, Vol.110 (9), pp. 3326-3333. show abstract
Chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders display familial aggregation. To identify a susceptibility gene for CLL, we assembled families from the major European (ICLLC) and American (GEC) consortia to conduct a genome-wide linkage analysis of 101 new CLL pedigrees using a high-density single nucleotide polymorphism (SNP) array and combined the results with data from our previously reported analysis of 105 families. Here, we report on the combined analysis of the 206 families. Multipoint linkage analyses were undertaken using both nonparametric (model-free) and parametric (model-based) methods. After the removal of high linkage disequilibrium SNPs, we obtained a maximum nonparametric linkage (NPL) score of 3.02 (P = .001) on chromosome 2q21.2. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a common recessive model of disease susceptibility (HLOD = 3.11; P = 7.7 x 10(-5)), which was significant at the genome-wide level. In addition, 2 other chromosomal positions, 6p22.1 (corresponding to the major histocompatibility locus) and 18q21.1, displayed HLOD scores higher than 2.1 (P < .002). None of the regions coincided with areas of common chromosomal abnormalities frequently observed in CLL. These findings provide direct evidence for Mendelian predisposition to CLL and evidence for the location of disease loci..
Hubner, R.A., Muir, K.R., Liu, J.-., Logan, R.F., Grainge, M.J., Houlston, R.S. & Members of the UKCAP Consortium, (2007). Polymorphisms in PTGS1, PTGS2 and IL-10 do not influence colorectal adenoma recurrence in the context of a randomized aspirin intervention trial. Int j cancer, Vol.121 (9), pp. 2001-2004. show abstract
Regular use of aspirin and other nonsteroidal antiinflammatory drugs reduces both the development of colorectal neoplasia and recurrence of colorectal adenoma (CRA). Modulation of the effects of aspirin by genetic factors has been reported, potentially allowing targeting of treatment to individuals most likely to gain benefit. Prostaglandin H synthase 1 (PTGS1) and PTGS2 are key enzymes in prostaglandin synthesis and are inhibited by aspirin, whilst interleukin-10 (IL-10) is an important antiinflammatory cytokine. We investigated whether functional genetic polymorphisms in the PTGS1, PTGS2 and IL-10 genes influence CRA recurrence in individuals participating in a randomized aspirin intervention trial. DNA was available for genotyping from 546 patients who received aspirin (300 mg daily) or placebo for a mean 41-months' duration. Homozygote carriers of variant alleles for the PTGS1 50C>T, PTGS2 -765G>C and IL-10 -592C>A polymorphisms did not have a significantly altered risk of CRA recurrence (relative risk [RR]=0.91; 95% confidence interval [CI]: 0.14-6.07, RR=1.32; 95% CI: 0.66-2.62 and RR=1.24; 95% CI: 0.74-2.07, respectively). There were also no significant interactions between aspirin intervention and genotype in determining recurrence risk. These data indicate that these polymorphisms are unlikely to influence CRA recurrence and cannot be used to identify individuals who derive benefit from aspirin intervention..
Hubner, R.A., Lubbe, S., Chandler, I. & Houlston, R.S. (2007). MTHFR C677T has differential influence on risk of MSI and MSS colorectal cancer. Hum mol genet, Vol.16 (9), pp. 1072-1077. show abstract
The majority of colorectal cancer (CRC) exhibiting the micosatellite instability (MSI) phenotype is due to hypermethylation of the hMLH1 gene promoter. We aimed to test the hypothesis that polymorphisms in genes coding for enzymes involved in folate metabolism play a role in altered promoter-specific hypermethylation and thus predispose to MSI CRC. Analysis of MSI was performed in 1685 CRCs, and polymorphism genotypes were determined in germline DNA for all cases and 2692 cancer-free controls. MSI was observed in 171 cancers (10.1%). Compared to homozygous wild-type individuals, those with MTHFR 677TT genotype were more likely to have MSI than microsatellite stable (MSS) CRC [odds ratio (OR) 1.90; 95% confidence interval (CI): 1.09-3.31]. When MTHFR C677T genotype frequencies in MSS CRC cases were compared to controls, individuals with homozygous variant genotype were at 19% reduced risk of cancer compared to wild type (OR = 0.81; 95% CI: 0.65-1.02). Conversely, when MSI CRC cases were compared to controls, individuals with one or two MTHFR 677T alleles were at 42% increased cancer risk (OR = 1.42; 95% CI: 1.02-1.96). Our observations indicate that MTHFR 677TT homozygous individuals are more likely to develop MSI CRC than those with wild-type genotype, and this common polymorphism has differential influences on MSI and MSS CRC risk. Stratification by MSI status should aid future studies investigating the complex relationships between genotype, environmental factors and CRC risk..
Popat, S., Zhao, D., Chen, Z., Pan, H., Shao, Y., Chandler, I. & Houlston, R.S. (2007). Relationship between chromosome 18q status and colorectal cancer prognosis: a prospective, blinded analysis of 280 patients. Anticancer res, Vol.27 (1B), pp. 627-633. show abstract
BACKGROUND: The relationship between chromosome 18q allelic imbalance (AI) and survival in colorectal cancer (CRC) is unclear, and study design may have contributed to inconsistent results previously reported. PATIENTS AND METHODS: Two hundred and eighty tumours from CRC patients participating in a molecular sub-study from a single multicentre trial of adjuvant intra-portal 5-fluorouracil were genotyped at 5 chromosome 18q microsatellite markers, blinded to clinical data and prospective to follow-up. The relationship between overall survival and AI was examined. RESULTS: Two hundred and fifty-five tumours were informative for AI. The overall rate of AI was 49%. AI was not associated with age, tumour site or size. There was no difference in five-year survival rate between patients with (60.0% SE 5.2%) and without AI (61.4% SE 5.0%), even after correcting for covariates (HR=1.17, 95%CI:0.79-1.74, p=0.4). CONCLUSION: Our data does not [corrected] support chromosome 18q AI as an important marker of survival in the adjuvant setting. It should not, therefore, be used outside clinical trials..
Hubner, R.A. & Houlston, R.S. (2007). MTHFR C677T and colorectal cancer risk: A meta-analysis of 25 populations. Int j cancer, Vol.120 (5), pp. 1027-1035. show abstract
The common functional methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may influence the risk of colorectal cancer (CRC), but data from published studies with individually low statistical power are conflicting. To clarify the role of MTHFR C677T genotype in CRC, we considered all available studies in a meta-analysis. Studies reporting on MTHFR C677T genotype and CRC were searched in PubMed up to April 2006. The principle prior hypothesis was that homozygosity for MTHFR 677TT would be associated with reduced risk of CRC. Data were available for 29,931 subjects, including 12,243 with CRC, from 25 independent populations. Compared to the homozygous CC genotype, the MTHFR 677TT genotype was associated with a reduced risk of CRC (odds ratio (OR): 0.83; 95% confidence interval (CI): 0.75-0.93; p = 0.001). There was some heterogeneity among the results of individual studies, but this was not statistically significant (heterogeneity p = 0.12; I2 = 25.8%). Heterozygosity for MTHFR 677 did not influence CRC risk (OR: 0.99; 95% CI: 0.94-1.04). These findings indicate that individuals homozygous for the MTHFR 677TT genotype are at moderately reduced risk of CRC, and support the proposal that common genetic variation in the MTHFR gene contributes to CRC susceptibility, probably accounting for at least 9% of the total incidence..
Popat, S., Zhao, D.B., Chen, Z.M., Pan, H.C., Sha, Y.F., Chandler, I. & Houlston, R.S. (2007). Relationship between chromosome 18q status and colorectal cancer prognosis: A prospective, blinded analysis of 280 patients (vol 27, pg 627, 2007). Anticancer res, Vol.27 (2), pp. 1231-1231.
Hubner, R.A. & Houlston, R.S. (2007). Re: MLH1 93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer. J natl cancer inst, Vol.99 (19), p. 1490.
Bethke, L., Webb, E., Sellick, G., Rudd, M., Penegar, S., Withey, L., Qureshi, M. & Houlston, R. (2007). Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk. Bmc cancer, Vol.7, p. 123. show abstract
BACKGROUND: Cytochrome P450 (CYP) enzymes have the potential to affect colorectal cancer (CRC) risk by determining the genotoxic impact of exogenous carcinogens and levels of sex hormones. METHODS: To investigate if common variants of CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1 and CYP19A1 influence CRC risk we genotyped 2,575 CRC cases and 2,707 controls for 20 single nucleotide polymorphisms (SNPs) that have not previously been shown to have functional consequence within these genes. RESULTS: There was a suggestion of increased risk, albeit insignificant after correction for multiple testing, of CRC for individuals homozygous for CYP1B1 rs162558 and heterozygous for CYP1A2 rs2069522 (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03-1.80 and OR = 1.34, 95% CI: 1.00-1.79 respectively). CONCLUSION: This study provides some support for polymorphic variation in CYP1A2 and CYP1B1 playing a role in CRC susceptibility..
Penegar, S., Wood, W., Lubbe, S., Chandler, I., Broderick, P., Papaemmanuil, E., Sellick, G., Gray, R., Peto, J. & Houlston, R., et al. (2007). National study of colorectal cancer genetics. Br j cancer, Vol.97 (9), pp. 1305-1309. show abstract
Approximately, a third of all colorectal cancer (CRC) is due to inherited susceptibility. However, high-risk mutations in APC, the mismatch repair (MMR) genes, MUTYH/MYH, SMAD4, ALK3 and STK11/LKB1 are rare and account for <5% of cases. Much of the remaining variation in genetic risk is likely to be explained by combinations of more common gene variants that modestly increase risk. Reliable identification of such 'low penetrance' alleles would provide insight into the aetiology of CRC and might highlight potential therapeutic and preventative interventions. In 2003, the National Study of Colorectal Cancer Genetics (NSCCG) was established with the aim of collecting DNA and clinicopathological data from 20,000 CRC cases and a series of spouse/partner controls, thereby creating a unique resource for identifying low-penetrance CRC susceptibility alleles. The National Cancer Research Network (NCRN) adopted NSCCG onto its portfolio of trials and 148 centres in the United Kingdom (UK) are now actively participating. Over 8,700 cases and 2,185 controls have so far been entered into NSCCG. Our experience in developing NSCCG serves to illustrate how world-class DNA databases for genetic analyses can be rapidly developed in the United Kingdom..
Sellick, G.S., Qureshi, M., Fielding, S., Catovsky, D. & Houlston, R.S. (2007). Germline mutations in SPI1 and MADD do not contribute to familial chronic lymphocytic leukaemia. Leukemia, Vol.21 (6), pp. 1315-1318.
Sellick, G.S., Lubbe, S.J., Matutes, E., Catovsky, D. & Houlston, R.S. (2007). Microsatellite instability indicative of defects in the major mismatch repair genes is rare in patients with B-cell chronic lymphocytic leukemia: Evaluation with disease stage and family history. Leuk lymphoma, Vol.48 (7), pp. 1320-1322. show abstract
A possible role for DNA mismatch repair defects and microsatellite instability (MSI) in the pathogenesis of a number of B-cell lymphoproliferative disorders has recently been debated. To gain further insight into the impact of MSI on B-CLL, we evaluated samples from a series of 982 patients using the mono-satellite markers BAT25 and BAT26, which are highly sensitive in demonstrating classical mismatch repair (MMR) deficiency. Only 1% of cases displayed MSI and this was not correlated with stage of disease or family history of B-CLL. A sub-polymorphic germline variant of BAT25 was identified in one familial case, which was also detected in the patient's affected brother. In conclusion, our study demonstrates that MSI does not have a prominent role in the pathogenesis of B-CLL..
Tomlinson, I., Webb, E., Carvajal-Carmona, L., Broderick, P., Kemp, Z., Spain, S., Penegar, S., Chandler, I., Gorman, M., Wood, W., et al. (2007). A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24 21. Nat genet, Vol.39 (8), pp. 984-988. show abstract
Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome- wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia..
Matakidou, A., El Galta, R., Webb, E.L., Rudd, M.F., Bridle, H., Eisen, T., Houlston, R.S. & GELCAPS Consortium, (2007). Lack of evidence that p53 Arg72Pro influences lung cancer prognosis: an analysis of survival in 619 female patients. Lung cancer, Vol.57 (2), pp. 207-212. show abstract
The prognostic significance of the Arg72Pro polymorphism of the p53 tumour suppressor gene in cancer is controversial. To determine whether Arg72Pro is a marker for lung cancer prognosis we genotyped 619 female lung cancer patients with incident disease and examined the relationship between genotype and overall survival (OS). Nonparametric tests provided no evidence for a relationship between SNP genotype and OS (P-values 0.131, 0.161, and 0.156 for log rank, Wilcoxon and Fleming-Harrington test statistics, respectively). Under the Cox proportional hazards model the HRs associated with Arg/Pro, Pro/Pro and Pro-carrier status were: 0.98 (95%CI: 0.79-1.22), 0.76 (95%CI: 0.51-1.15) and 0.93 (95%CI: 0.76-1.15), respectively. Despite employing a comprehensive set of statistical tests including those sensitive to the detection of differences in early survival our data provide little evidence to support the tenet that the p53 Arg72Pro polymorphism is a clinically useful prognostic marker for lung cancer..
Malmer, B., Adatto, P., Armstrong, G., Barnholtz-Sloan, J., Bernstein, J.L., Claus, E., Davis, F., Houlston, R., Il'yasova, D., Jenkins, R., et al. (2007). GLIOGENE - an international consortium to understand familial glioma. Cancer epidemiology biomarkers & prevention, Vol.16 (9), pp. 1730-1734.
Broderick, P., Carvajal-Carmona, L., Pittman, A.M., Webb, E., Howarth, K., Rowan, A., Lubbe, S., Spain, S., Sullivan, K., Fielding, S., et al. (2007). A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat genet, Vol.39 (11), pp. 1315-1317. show abstract
To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-beta and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (P(trend) = 1.0 x 10(-12))..
Skoglund, J., Song, B., Dalén, J., Dedorson, S., Edler, D., Hjern, F., Holm, J., Lenander, C., Lindforss, U., Lundqvist, N., et al. (2007). Lack of an association between the TGFBR1*6A variant and colorectal cancer risk. Clin cancer res, Vol.13 (12), pp. 3748-3752. show abstract
PURPOSE: Recently a common variant of the TGFBR1 gene, TGFBR1*6A, has been proposed to act as a low-penetrance tumor susceptibility allele for colorectal cancer, but data from published studies with individually low statistical power are conflicting. To further evaluate the relationship between TGFBR1*6A and colorectal cancer risk, we have conducted a large case-control study and a meta-analysis of previously published studies. EXPERIMENTAL DESIGN: A total of 1,042 colorectal cancer cases and 856 population controls were genotyped for the TGFBR1*6A polymorphism. Previously published case-control studies of the relationship between TGFBR1*6A and colorectal cancer were identified, and a meta-analysis was conducted. RESULTS: We found no evidence that homozygosity, heterozygosity or carrier status for the TGFBR1*6A allele confers an increased risk of colorectal cancer; respective odds ratios (OR) were 1.05 [95% confidence interval (95% CI), 0.83-1.32], 0.82 (95% CI, 0.34-1.99), and 0.92 (95% CI, 0.74-1.15), respectively. A meta-analysis of our case-control study and seven other studies that provided data on 2,627 colorectal cancer cases and 3,387 controls also yielded no evidence that possession of the TGFBR1*6A allele is associated with an elevated risk of colorectal cancer; pooled estimate of the OR were 1.20 (95% CI, 0.64-2.24) for homozygosity, 1.11 (95% CI, 0.96-1.29) for heterozygosity, and 1.13 (95% CI, 0.98-1.30) for carriers of TGFBR1*6A. CONCLUSION: Current data provide limited support for the hypothesis that sequence variation in TGFBR1 defined by the TGFBR1*6A allele confers an elevated risk of colorectal cancer..
Matakidou, A., El Galta, R., Rudd, M.F., Webb, E.L., Bridle, H., Eisen, T. & Houlston, R.S. (2007). Prognostic significance of folate metabolism polymorphisms for lung cancer. Br j cancer, Vol.97 (2), pp. 247-252. show abstract
Functional nonsynonymous single-nucleotide polymorphisms (nsSNPs) of folate metabolism genes can influence the methylation of tumour suppressor genes, thereby potentially impacting on tumour behaviour. To investigate whether such polymorphisms influence lung cancer survival, we genotyped 14 nsSNPs mapping to methylene-tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR); DNA methyltransferase (DNMT2), methylenetetrahydrofolate dehydrogenase (MTHFD1) and methenyltetrahydrofolate synthetase (MTHFS) in 619 Caucasian women with incident disease, 465 with non-small cell (NSCLC) and 154 with small cell lung cancer (SCLC). The most significant association detected was with MTHFS Thr202Ala, with carriers of variant alleles having a worse prognosis (hazard ratio (HR)=1.49; 95% confidence interval: 1.14-1.94). Associations were also detected between overall survival (OS) in SCLC and homozygosity for MTHFR 222Val (HR=1.92; 1.03-3.58) and between OS from NSCLC and MTRR 175Leu carrier status (HR=1.36; 1.06-1.75). While there is evidence that variation in the folate metabolism genes may influence prognosis from lung cancer, current data are insufficiently robust to distinguish individual patient outcome..
Matakidou, A., El Galta, R., Rudd, M.F., Webb, E.L., Bridle, H., Eisen, T. & Houlston, R.S. (2007). Further observations on the relationship between the FGFR4 Gly388Arg polymorphism and lung cancer prognosis. Br j cancer, Vol.96 (12), pp. 1904-1907. show abstract
The Gly388Arg polymorphism in the fibroblast growth factor receptor 4 (FGFR4) gene has been reported to influence prognosis in a wide variety of cancer types. To determine whether Gly388Arg is a marker for lung cancer prognosis, we genotyped 619 lung cancer patients with incident disease and examined the relationship between genotype and overall survival. While we employed a comprehensive set of statistical tests, including those sensitive to the detection of differences in early survival, our data provide little evidence to support the tenet that the FGFR4 Gly388Arg polymorphism is a clinically useful marker for lung cancer prognosis..
Hubner, R.A., Liu, J.-., Sellick, G.S., Logan, R.F., Houlston, R.S. & Muir, K.R. (2007). Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma. Br j cancer, Vol.97 (10), pp. 1449-1456. show abstract
The effects of polymorphisms in genes coding for key folate metabolism enzymes such as thymidylate synthetase (TS) on colorectal neoplasia risk are likely to be influenced by gene-gene and gene-nutrient interactions. We investigated the combined effects of three polymorphisms in the TS gene region, TSER, TS 3R G>C, and TS 1494del6, dietary intakes of folate and other B vitamins, and genotype for other folate metabolism variants, in a colorectal adenoma (CRA) case-control study. Individuals homozygous for TS 1494del6 del/del were at significantly reduced CRA risk compared to those with either ins/del or ins/ins genotypes (odds ratio 0.52; 95% confidence interval: 0.31-0.85, P=0.009). We also observed evidence of interactions between TS 1494del6 genotype and intake of folate, and vitamins B6 and B12, and MTHFR C677T genotype, with the reduction in risk in del/del homozygotes being largely confined to individuals with high nutrient intakes and MTHFR 677CC genotype (P interaction=0.01, 0.006, 0.03, and 0.07, respectively). TSER genotype, when considered either alone or in combination with TS 3R G>C genotype, did not significantly influence CRA risk. These findings support a role for TS in colorectal carcinogenesis, and provide further evidence that functional polymorphisms in folate metabolism genes act as low-risk alleles for colorectal neoplasia and participate in complex gene-gene and gene-nutrient interactions..
Jonsson, V., Tjonnfjord, G., Samuelsen, S.O., Johannesen, T., Olsen, J., Sellick, G., Houlston, R., Yuille, M. & Catovsky, D. (2007). Birth order pattern in the inheritance of chronic lymphocytic leukaemia and related lymphoproliferative disease. Leukemia & lymphoma, Vol.48 (12), pp. 2387-2396.
Tjellstroem, B., Stenhammar, L., Hoegberg, L., Faelth-Magnusson, K., Magnusson, K.-., Midtvedt, T., Sundqvist, T., Houlston, R., Popat, S. & Norin, E., et al. (2007). Gut microflora associated characteristics in first-degree relatives of children with celiac disease. Scandinavian journal of gastroenterology, Vol.42 (10), pp. 1204-1208.
Webb, E.L. & Houlston, R.S. (2007). Association studies using familial cases: an efficient strategy for identifying low-penetrance disease alleles. Methods mol biol, Vol.376, pp. 151-159. show abstract
Low-penetrance alleles are likely to contribute to inherited susceptibility to many complex traits. Such alleles will rarely generate multiple-case families and are therefore difficult or impossible to identify through genetic linkage analyses. The search for low-penetrance alleles has therefore centred on comparing the frequencies of specific alleles in cases and controls via an association study. With recent improvements in genotyping technology and cost, and the completion of the HapMap Project, the long-predicted era of whole-genome association studies is now upon us, with several large-scale studies underway. Such studies require the simultaneous performance of a large number of statistical tests, with the result that power to detect association is in short supply, particularly if the disease allele is rare. One strategy to increase the power of an association study is to enrich cases for genetic predisposition; for this purpose, studies based on familial cases have attracted considerable interest. Using cancer as an example of a complex trait, we show that this approach greatly increases the power to detect association under a range of modes of inheritance, relative risks, and allele frequencies, but is especially efficient for detection of rare alleles..
Webb, E.L., Rudd, M.F., Sellick, G.S., El Galta, R., Bethke, L., Wood, W., Fletcher, O., Penegar, S., Withey, L., Qureshi, M., et al. (2006). Search for low penetrance alleles for colorectal cancer through a scan of 1467 non-synonymous SNPs in 2575 cases and 2707 controls with validation by kin-cohort analysis of 14 704 first-degree relatives. Hum mol genet, Vol.15 (21), pp. 3263-3271. show abstract
To identify low penetrance susceptibility alleles for colorectal cancer (CRC), we genotyped 1467 non-synonymous SNPs mapping to 871 candidate cancer genes in 2575 cases and 2707 controls. nsSNP selection was biased towards those predicted to be functionally deleterious. One SNP AKAP9 M463I remained significantly associated with CRC risk after stringent adjustment for multiple testing. Further SNPs associated with CRC risk included several previously reported to be associated with cancer risk including ATM F858L [OR=1.48; 95% confidence interval (CI): 1.06-2.07] and P1054R (OR=1.42; 95% CI: 1.14-1.77) and MTHFR A222V (OR=0.82; 95% CI: 0.69-0.97). To validate associations, we performed a kin-cohort analysis on the 14 704 first-degree relatives of cases for each SNP associated at the 5% level in the case-control analysis employing the marginal maximum likelihood method to infer genotypes of relatives. Our observations support the hypothesis that inherited predisposition to CRC is in part mediated through polymorphic variation and identify a number of SNPs defining inter-individual susceptibility. We have made data from this analysis publicly available at http://www.icr.ac.uk/research/research_sections/cancer_genetics/ cancer_genetics_teams/molecular_and_population_genetics/software_and_databases/index.shtml in order to facilitate the identification of low penetrance CRC susceptibility alleles through pooled analyses..
Hubner, R.A., Muir, K.R., Liu, J.-., Logan, R.F., Grainge, M., Armitage, N., Shepherd, V., Popat, S., Houlston, R.S. & United Kingdom Colorectal Adenoma Prevention Consortium, , et al. (2006). Genetic variants of UGT1A6 influence risk of colorectal adenoma recurrence. Clin cancer res, Vol.12 (21), pp. 6585-6589. show abstract
PURPOSE: The UDP glucuronosyltransferase 1A6 (UGT1A6) and cytochrome P450 2C9 (CYP2C9) enzymes participate in the metabolism of nonsteroidal anti-inflammatory drugs, endogenous substances, and carcinogens. Functional polymorphisms of UGT1A6 (T181A and R184S) and CYP2C9 (R144C and I359L) have been reported to modify the protective effect of aspirin on colorectal adenoma risk. We aimed to further investigate the effect of these genetic variants on the development of colorectal neoplasia. EXPERIMENTAL DESIGN: We examined the relationship between UGT1A6 and CYP2C9 genotype and colorectal adenoma recurrence in 546 patients participating in a randomized placebo-controlled aspirin intervention trial. RESULTS: Although colorectal adenoma recurrence was not significantly influenced by CYP2C9 genotype, carriers of variant UGT1A6 alleles were at significantly reduced risk of colorectal neoplasia recurrence [relative risk (RR), 0.68; 95% confidence interval (95% CI), 0.52-0.89]. This risk reduction was also evident when the analysis was confined to advanced neoplasia recurrence (RR, 0.71; 95% CI, 0.47-1.09). When patients were stratified by genotype and aspirin intervention, those with variant UGT1A6 alleles were at reduced recurrence risk irrespective of whether they received aspirin or placebo (RR, 0.62; 95% CI, 0.42-0.92 and RR, 0.63; 95% CI, 0.44-0.91, respectively). CONCLUSIONS: These findings confirm that UGT1A6 variants influence colorectal carcinogenesis independent of aspirin intake and suggest that they may have clinical value in secondary prevention programs for patients diagnosed with colorectal adenoma..
To identify low penetrance susceptibility alleles for colorectal cancer (CRC), we genotyped 1467 non-synonymous SNPs mapping to 871 candidate cancer genes in 2575 cases and 2707 controls. nsSNP selection was biased towards those predicted to be functionally deleterious. One SNP AKAP9 M463I remained significantly associated with CRC risk after stringent adjustment for multiple testing. Further SNPs associated with CRC risk included several previously reported to be associated with cancer risk including ATM F858L [OR=1.48; 95% confidence interval (CI): 1.06-2.07] and P1054R (OR=1.42; 95% CI: 1.14-1.77) and MTHFR A222V (OR=0.82; 95% CI: 0.69-0.97). To validate associations, we performed a kin-cohort analysis on the 14 704 first-degree relatives of cases for each SNP associated at the 5% level in the case-control analysis employing the marginal maximum likelihood method to infer genotypes of relatives. Our observations support the hypothesis that inherited predisposition to CRC is in part mediated through polymorphic variation and identify a number of SNPs defining inter-individual susceptibility. We have made data from this analysis publicly available at http://www.icr.ac.uk/research/research_sections/cancer_genetics/cancer_genetics_teams/molecular_and_population_genetics/software_and_databases/index.shtml in order to facilitate the identification of low penetrance CRC susceptibility alleles through pooled analyses..
Kemp, Z., Carvajal-Carmona, L., Spain, S., Barclay, E., Gorman, M., Martin, L., Jaeger, E., Brooks, N., Bishop, D.T., Thomas, H., et al. (2006). Evidence for a colorectal cancer susceptibility locus on chromosome 3q21-q24 from a high-density SNP genome-wide linkage scan. Hum mol genet, Vol.15 (19), pp. 2903-2910. show abstract
To identify a novel susceptibility gene for colorectal cancer (CRC), we conducted a genome-wide linkage analysis of 69 pedigrees segregating colorectal neoplasia in which involvement of known loci had been excluded, using a high-density single nucleotide polymorphism (SNP) array containing 10,204 markers. Multipoint linkage analyses were undertaken using both non-parametric (model-free) and parametric (model-based) methods. After the removal of SNPs in strong linkage disequilibrium, we obtained a maximum non-parametric linkage statistic of 3.40 (P=0.0003) at chromosomal region 3q21-q24. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=3.10, genome-wide P=0.038) with 62% of families linked to the locus. We provide evidence for a novel CRC susceptibility gene. Further studies are needed to confirm this localization and to evaluate the contribution of this locus to disease incidence..
Sellick, G.S., Catovsky, D. & Houlston, R.S. (2006). Familial chronic lymphocytic leukemia. Semin oncol, Vol.33 (2), pp. 195-201. show abstract
The role of inherited genetic factors in the etiology of chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders (LPDs) is now well established. Significant familial aggregation of CLL and B-cell LPDs has been demonstrated, but the mode of inheritance is unknown. Identifying genes that when mutated confer an increased risk of these diseases is of immediate clinical relevance in terms of primary and secondary interventions. Furthermore, their identification provides for a greater understanding of the mechanisms of B-cell tumorigenesis in general. Here we review the current status of knowledge relating to inherited susceptibility to CLL and the strategies that are being employed to identify disease-causing mutations..
Hearle, N.C., Rudd, M.F., Lim, W., Murday, V., Lim, A.G., Phillips, R.K., Lee, P.W., O'donohue, J., Morrison, P.J., Norman, A., et al. (2006). Exonic STK11 deletions are not a rare cause of Peutz-Jeghers syndrome. J med genet, Vol.43 (4), p. e15. show abstract
BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant cancer predisposition syndrome characterised by oro-facial pigmentation and hamartomatous polyposis of the gastrointestinal tract. A causal germline mutation in STK11 can be identified in 30% to 80% of PJS patients. METHODS: Here we report the comprehensive mutational analysis of STK11 in 38 PJS probands applying conventional PCR based mutation detection methods and the recently introduced MLPA (multiplex ligation dependent probe amplification) technique developed for the identification of exonic deletions/duplications. RESULTS: Nineteen of 38 probands (50%) had detectable point mutations or small scale deletions/insertions and six probands (16%) had genomic deletions encompassing one or more STK11 exons. CONCLUSIONS: These findings demonstrate that exonic STK11 deletions are a common cause of PJS and provide a strong rationale for conducting a primary screen for such mutations in patients..
de Tute, R., Yuille, M., Catovsky, D., Houlston, R.S., Hillmen, P. & Rawstron, A.C. (2006). Monoclonal B-cell lymphocytosis (MBL) in CLL families: substantial increase in relative risk for young adults. Leukemia, Vol.20 (4), pp. 728-729.
Popat, S., Wort, R. & Houlston, R.S. (2006). Inter-relationship between microsatellite instability, thymidylate synthase expression, and p53 status in colorectal cancer: implications for chemoresistance. Bmc cancer, Vol.6, p. 150. show abstract
BACKGROUND: Studies indicate that thymidylate synthase (TS) expression, p53 and mismatch repair status have potential to influence colorectal cancer (CRC) outcome. There is, however, little data on the inter-relationship between these three markers. We sought to investigate whether relationships exist between these markers that might contribute to CRC phenotypes. METHODS: Four hundred and forty-one stage I-III CRCs were investigated. p53 status and TS expression were assessed by standard immunohistochemistry methods. Mismatch repair status was determined by assessment of microsatellite instability (MSI) using radiolabelled microsatellite genotyping. RESULTS: 244 tumours (55%) over-expressed p53, and 259 (58%) expressed high TS levels. 65 tumours (15%) had MSI. A significant relationship between p53 over-expression and high TS expression was observed (p = 0.01). This was independent of MSI status. A highly significant inverse relationship between MSI and p53 status was observed (p = 0.001). No relationship was seen between MSI status and TS expression (p = 0.59). CONCLUSION: Relationships exist between p53 status and TS expression, and MSI and p53 status. These inter-relationships may contribute to the clinical phenotype of CRCs associated with each of the molecular markers. High TS expression is unlikely to account for the clinical behaviour of CRCs with MSI..
Rudd, M.F., Webb, E.L., Matakidou, A., Sellick, G.S., Williams, R.D., Bridle, H., Eisen, T., Houlston, R.S. & GELCAPS Consortium, (2006). Variants in the GH-IGF axis confer susceptibility to lung cancer. Genome res, Vol.16 (6), pp. 693-701. show abstract
We conducted a large-scale genome-wide association study in UK Caucasians to identify susceptibility alleles for lung cancer, analyzing 1529 cases and 2707 controls. To increase the likelihood of identifying disease-causing alleles, we genotyped 1476 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 871 candidate cancer genes, biasing SNP selection toward those predicted to be deleterious. Statistically significant associations were identified for 64 nsSNPs, generating a genome-wide significance level of P=0.002. Eleven of the 64 SNPs mapped to genes encoding pivotal components of the growth hormone/insulin-like growth factor (GH-IGF) pathway, including CAMKK1 E375G (OR=1.37, P=5.4x10(-5)), AKAP9 M463I (OR=1.32, P=1.0x10(-4)) and GHR P495T (OR=12.98, P=0.0019). Significant associations were also detected for SNPs within genes in the DNA damage-response pathway, including BRCA2 K3326X (OR=1.72, P=0.0075) and XRCC4 I137T (OR=1.31, P=0.0205). Our study provides evidence that inherited predisposition to lung cancer is in part mediated through low-penetrance alleles and specifically identifies variants in GH-IGF and DNA damage-response pathways with risk of lung cancer..
Almeida, A.M., Murakami, Y., Layton, D.M., Hillmen, P., Sellick, G.S., Maeda, Y., Richards, S., Patterson, S., Kotsianidis, I., Mollica, L., et al. (2006). Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency. Nature medicine, Vol.12 (7), pp. 846-851.
Barker, K.T., Foulkes, W.D., Schwartz, C.E., Labadie, C., Monsell, F., Houlston, R.S. & Harper, J. (2006). Is the E133K allele of VG5Q associated with Klippel-Trenaunay and other overgrowth syndromes?. J med genet, Vol.43 (7), pp. 613-614. show abstract
BACKGROUND: It has been reported that the activating mutation, E133K, in the angiogenic factor VG5Q (formally named AGGF1) causes Klippel-Trenaunay Syndrome (KTS), a rare vascular disease associated with asymmetric overgrowth. This proposal followed from the observation that five out of 130 KTS patients were constitutionally heterozygous for VG5Q, E133K. OBJECTIVE: To explore the possibility that VG5Q, and specifically E133K, is implicated in other mosaic overgrowth syndromes. RESULTS: 24 patients were analysed for this sequence change. One patient was constitutionally heterozygous for E133K. Analysis of both parents revealed that the patient's mother, who was healthy, also carried E133K. An analysis of 275 healthy controls showed that 3.3% (9/275) of the population were carriers of E133K. CONCLUSIONS: The findings bring into question the assertion that VG5Q, E133K is a mutation and that it causes KTS..
Jønsson, V., Bock, J.E., Hilden, J., Houlston, R.S. & Wiik, A. (2006). The influence of pregnancy on the development of autoimmunity in chronic lymphocytic leukemia. Leuk lymphoma, Vol.47 (8), pp. 1481-1487. show abstract
To examine whether pregnancy influences the development of autoimmunity in chronic lymphocytic leukemia (CLL), we studied 591 consecutive CLL patients (202 post-menopausal women and 389 men). The mean observation time for all patients was 3.8 years, corresponding to approximately 2200 person-years of follow-up. Autoimmune manifestations were analyzed in 194 women with known obstetric history and known number of long-term sexual partners, and in the 389 male CLL patients for comparison. One hundred and fifty-nine of the CLL patients exhibited autoimmune manifestations, 38% in females and 21% in men. In female CLL patients, the frequency of autoimmunity and the number of pregnancies and the number of partners were strongly correlated. Each of the major autoimmune types approximately doubled in frequency for each additional pregnancy. The impact of pregnancy on expressed autoimmunity increased with each additional sexual partner (the odds of autoimmunity increased 11 times with each long-term sexual partner). The average numbers of pregnancies in female CLL patients with and without autoimmunity were 4.92 and 2.24, respectively (P < 0.001). Coombs' positive autoimmune anemia, a gastric ulcer with parietal cell autoantibodies and idiopathic thrombocytopenic purpura were equally common in women and men, whereas autoimmune thyroiditis, Sjögren's syndrome, rheumatoid arthritis and systemic lupus erythematosus were seen in higher rates in women than in men. The spectrum of autoimmunity suggests that pregnancy-related alloimmunization may be involved in the development of autoimmunity in CLL..
Hearle, N., Schumacher, V., Menko, F.H., Olschwang, S., Boardman, L.A., Gille, J.J., Keller, J.J., Westerman, A.M., Scott, R.J., Lim, W., et al. (2006). STK11 status and intussusception risk in Peutz-Jeghers syndrome. J med genet, Vol.43 (8), p. e41. show abstract
BACKGROUND: Peutz-Jeghers syndrome (PJS) is caused by germline STK11 mutations and characterised by gastrointestinal polyposis. Although small bowel intussusception is a recognised complication of PJS, risk varies between patients. OBJECTIVE: To analyse the time to onset of intussusception in a large series of PJS probands. METHODS: STK11 mutation status was evaluated in 225 PJS probands and medical histories of the patients reviewed. RESULTS: 135 (60%) of the probands possessed a germline STK11 mutation; 109 (48%) probands had a history of intussusception at a median age of 15.0 years but with wide variability (range 3.7 to 45.4 years). Median time to onset of intussusception was not significantly different between those with identified mutations and those with no mutation detected, at 14.7 years and 16.4 years, respectively (log-rank test of difference, chi(2) = 0.58, with 1df; p = 0.45). Similarly no differences were observed between patient groups on the basis of the type or site of STK11 mutation. CONCLUSIONS: The risk of intussusception in PJS is not influenced by STK11 mutation status..
Hubner, R.A. & Houlston, R.S. (2006). Molecular advances in medullary thyroid cancer diagnostics. Clin chim acta, Vol.370 (1-2), pp. 2-8. show abstract
Germline activating mutations in the RET proto-oncogene cause inherited medullary thyroid cancer (MTC) and the multiple endocrine neoplasia type 2 (MEN2) syndrome. Identification of a RET mutation in an individual with MEN2 allows pre-symptomatic genetic testing of other at-risk family members, and guides early intervention to prevent death and serious morbidity from MTC. Developments in the understanding of downstream RET receptor signalling pathways and how activating mutations disturb receptor function has led to insights into the possible molecular mechanisms underlying the different MEN2 phenotypes. Mutation analysis of RET in individuals with MEN2 has identified a number of different mutations, and correlation with cancer biology and clinical outcome has led to tailoring of management according to the mutation detected..
Barker, K.T., Spendlove, H.E., Banu, N.S., Bridge, J.A., Fisher, C., Shipley, J., Garrett, M., Manyonda, I. & Houlston, R.S. (2006). No evidence for epigenetic inactivation of fumarate hydratase in leiomyomas and leiomyosarcomas. Cancer lett, Vol.235 (1), pp. 136-140. show abstract
Germline mutations in Fumarate Hydratase (FH) cause the development of leiomyomas and leiomyosarcomas in the syndromes Multiple Cutaneous and Uterine Leiomyomata (MCUL1) and Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). There is little evidence, however, that FH mutation plays a role in the development of sporadic leiomyomas or leiomyosarcomas. Such observations do not, however, exclude a role for FH in tumour development outside the context of MCUL1/HLRCC, as it is possible that FH expression could be silenced by epigenetic mechanisms. To explore this possibility we have developed a highly specific antibody to FH and analysed a series of forty-five fresh-frozen uterine leiomyomas and nine leiomyosarcomas for FH expression..
Lakhani, S.R., Audretsch, W., Cleton-Jensen, A.-., Cutuli, B., Ellis, I., Eusebi, V., Greco, M., Houslton, R.S., Kuhl, C.K., Kurtz, J., et al. (2006). The management of lobular carcinoma in situ (LCIS) Is LCIS the same as ductal carcinoma in situ (DCIS)?. European journal of cancer, Vol.42 (14), pp. 2205-2211.
Hughes, S., Williams, R.D., Webb, E. & Houlston, R.S. (2006). Meta-analysis and pooled re-analysis of copy number changes in colorectal cancer detected by comparative genomic hybridization. Anticancer res, Vol.26 (5A), pp. 3439-3444. show abstract
BACKGROUND: Comparative genomic hybridization (CGH) provides an insight into chromosomal changes associated with colorectal cancer (CRC) development. However, a problem with many studies is the limited cohort size, making the significance of some findings unclear. MATERIALS AND METHODS: To derive a better insight into the chromosomal changes associated with CRC, we performed a meta-analysis and pooled re-analysis of published metaphase CGH data. RESULTS: In addition to recurrent alterations, gains of 20 13q, 8q and 7p and loss of 18, 17p, 8p and 4p, pooling identified less frequent, but significant changes, including gain of 1q and 3, and losses from 6q, 9p and 21q. CONCLUSION: These additional alterations may be characteristic of some tumors and thus have relevance to CRC biology. Meta-analysis not only has the potential to detect novel changes, present at low frequency in several independent studies, but can provide greater reliability for their detection than single studies alone..
Broderick, P., Bagratuni, T., Vijayakrishnan, J., Lubbe, S., Chandler, I. & Houlston, R.S. (2006). Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition. Bmc cancer, Vol.6, p. 243. show abstract
BACKGROUND: The observation that germline mutations in the oxidative DNA damage repair gene MUTYH cause colorectal cancer (CRC) provides strong evidence that dysregulation of the base excision repair (BER) pathway influences disease susceptibility. It is conceivable that germline sequence variation in other BER pathway genes such as NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 also contribute to CRC susceptibility. METHODS: To evaluate whether sequence variants of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes might act as CRC susceptibility alleles, we screened the coding sequence and intron-exon boundaries of these genes in 94 familial CRC cases in which involvement of known genes had been excluded. RESULTS: Three novel missense variants were identified NEIL2 C367A, TDG3 A196G and UNG2 C262T in patients, which were not observed in 188 healthy control DNAs. CONCLUSION: We detected novel germline alterations in NEIL2, TDG and UNG patients with CRC. The results suggest a limited role for NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 in development of CRC..
Hubner, R.A., Muir, K.R., Liu, J.-., Sellick, G.S., Logan, R.F., Grainge, M., Armitage, N., Chau, I. & Houlston, R.S. (2006). Folate metabolism polymorphisms influence risk of colorectal adenoma recurrence. Cancer epidemiol biomarkers prev, Vol.15 (9), pp. 1607-1613. show abstract
Folate intake is inversely related to risk of developing colorectal neoplasia. Associations between risk of colorectal neoplasia and polymorphisms in genes coding for enzymes involved in folate metabolism have also been reported, suggesting a relationship between genotype and development of colorectal neoplasia. To further investigate the effects of folate metabolism genotypes on colorectal neoplasia, we genotyped 546 patients participating in a randomized controlled trial of folate supplementation for the prevention of colorectal adenoma recurrence. A significantly reduced risk of recurrence was observed in patients heterozygous for the MTRR A66G polymorphism [relative risk (RR), 0.64; 95% confidence interval (95% CI), 0.46-0.90] or heterozygous for the MTHFR A1298C polymorphism (RR, 0.71; 95% CI, 0.52-0.97). Furthermore, a significant reduction in recurrence risk was seen in MTRR A66G heterozygotes who received folate supplements but not in those who did not receive folate. Patients heterozygous for the MTHFR C677T polymorphism had a nonsignificant risk reduction (RR, 0.92; 95% CI, 0.69-1.23), as did patients with one or two variant alleles for the MTR A2756G polymorphism (RR, 0.82; 95% CI, 0.60-1.12). No influence on recurrence risk was observed for the TSER, TSER 3R G>C, and TS 1494del6 variants. These findings provide additional support for the hypothesis that germ line variants in folate metabolism genes influence the development of colorectal adenomas..
Webb, E.L., Rudd, M.F. & Houlston, R.S. (2006). Colorectal cancer risk in monoallelic carriers of MYH variants. Am j hum genet, Vol.79 (4), pp. 768-771.
Sellick, G.S., Hoornaert, K.P., Mortier, G.R., King, C., Dolling, C.L., Newbury-Ecob, R.A., Gargan, M., Hall, C.M., Houlston, R.S. & Smithson, S.F., et al. (2006). A form of autosomal dominant spondyloepiphyseal dysplasia is caused by a glycine to alanine substitution in the COL2A1 gene. Clin dysmorphol, Vol.15 (4), pp. 197-202. show abstract
We report a family with an unusual form of autosomal dominant spondyloepiphyseal dysplasia characterized by infantile-onset disproportionate short stature with relative shortening of the spine, thoracic kyphosis, lumbar lordosis, scoliosis and premature osteoarthritis of the joints especially of the hips. Radiological findings include mild platyspondyly, vertebral end plate irregularity, irregular femoral necks, and dysplasia of the capital femoral epiphyses with flattening and irregularity present from childhood and mild variable epiphyseal dysplasia elsewhere in the skeleton. Intrafamilial variability is observed in the degree of short stature, severity of spinal and hip involvement and the age of onset of symptoms and complications. We demonstrate that this dysplasia is due to a glycine to alanine substitution in the COL2A1 gene (p.Gly862Ala), thereby expanding the phenotypic spectrum of dysplasias associated with defects in type II collagen..
Thompson, D., Seal, S., Schutte, M., McGuffog, L., Barfoot, R., Renwick, A., Eeles, R., Sodha, N., Houlston, R., Shanley, S., et al. (2006). A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer epidem biomar, Vol.15 (12), pp. 2542-2545. show abstract
The CHEK2 1100delC protein-truncating mutation has a carrier frequency of similar to 0.7% in Northern and Western European populations and confers an similar to 2-fold increased risk of breast cancer. It has also been suggested to increase risks of colorectal and prostate cancer, but its involvement with these or other types of cancer has not been confirmed. The incidence of cancer other than breast cancer in 11,116 individuals from 734 non-BRCA1/2 breast cancer families from the United Kingdom, Germany, Netherlands, and the United States was compared with that predicted by population rates. Relative risks (RR) to carriers and noncarriers were estimated by maximum likelihood, via the expectation-maximization algorithm to allow for unknown genotypes. Sixty-seven families contained at least one tested CHEK2 1100delC mutation carrier. There was evidence of underreporting of cancers in male relatives (422 cancers observed, 860 expected) but not in females (322 observed, 335 expected); hence, we focused on cancer risks in female carriers. The risk of cancers other than breast cancer in female carriers was not significantly elevated, although a modest increase in risk could not be excluded (RR, 1.18; 95% confidence interval, 0.64-2.17). The carrier risk was not significantly raised for any individual cancer site, including colorectal cancer (RR, 1.60; 95% confidence interval, 0.54-4.71). However, between ages 20 to 50 years, the risks of colorectal and lung cancer were both higher in female carriers than noncarriers (P = 0.041 and 0.0001, respectively). There was no evidence of a higher prostate cancer risk in carriers than noncarriers (P = 0.26), although underreporting of male cancers limited our power to detect such a difference. Our results suggest that the risk of cancer associated with CHEK2 1100delC mutations is restricted to breast cancer, although we cannot rule out a small increase in overall cancer risk..
Popat, S., Chen, Z., Zhao, D., Pan, H., Hearle, N., Chandler, I., Shao, Y., Aherne, W. & Houlston, R.S. (2006). A prospective, blinded analysis of thymidylate synthase and p53 expression as prognostic markers in the adjuvant treatment of colorectal cancer. Ann oncol, Vol.17 (12), pp. 1810-1817. show abstract
Background: Despite previous studies, uncertainty has persisted about the role of thymidylate synthase (TS) and p53 status as markers of prognosis in colorectal cancer (CRC).Patients and methods: A total of 967 patients accrued to a large adjuvant trial in CRC were included in a prospectively planned molecular substudy, and of them, 59% had rectal cancer and about 90% received adjuvant chemotherapy (either systemically or randomly allocated to intraportal 5-fluorouracil infusion or both). TS and p53 status were determined, blinded to any clinical data, by immunohistochemistry using a validated polyclonal antibody or the DO-7 clone, respectively, and their relationships with overall survival were examined.Results: High TS expression was observed in 58% and overexpression of p53 in 60% of tumours. TS expression correlated with tumour stage, and p53 overexpression, with rectal cancers. There was no evidence that either marker was significantly associated with survival by either univariate (TS hazard ratio (HR) = 0.94, 95% CI 0.76-1.18 and P = 0.6 and p53 HR = 0.98, 95% CI 0.78-1.23 and P = 0.9) or multivariate analyses (TS HR = 0.99, 95% CI 0.79-1.25 and P = 0.9 and p53 HR = 0.98, 95% CI 0.78-1.23 and P = 0.8).Conclusions: Neither TS nor p53 expression has significant prognostic value in the adjuvant setting of CRC..
Sellick, G.S., Sullivan, K., Catovsky, D. & Houlston, R.S. (2006). CHEK2*1100delC and risk of chronic lymphocytic leukemia. Leuk lymphoma, Vol.47 (12), pp. 2659-2660.
Sellick, G.S., Catovsky, D. & Houlston, R.S. (2006). Relationship between ARLTS1 polymorphisms and risk of chronic lymphocytic leukemia. Leuk res, Vol.30 (12), pp. 1573-1576. show abstract
ARLTS1, a member of the Ras superfamily and putative tumor-suppressor gene resides at chromosome 13q14, a region commonly deleted in hematopoietic and solid tumors. Previously, the truncating single nucleotide polymorphism (SNP) of ARLTS, G446A (W149X) has been reported to act as a multi-site tumor susceptibility allele. To explore the relationship between polymorphic variation in ARTLS1 and risk of chronic lymphocytic leukemia (CLL) we analyzed germline DNA from 413 cases and 471 healthy controls for W149X and five additional coding SNPs, S99S, P131L, L132L, C148R, and E164K. A high proportion of the cases were familial, thereby empowering detection of an association. None of the SNPs were individually significantly associated with risk of CLL and there was no evidence for epistatic interaction between loci. Our study does not support the postulate that variants of ARLTS1 influence the risk of CLL..
Kemp, Z.E., Carvajal-Carmona, L.G., Barclay, E., Gorman, M., Martin, L., Wood, W., Rowan, A., Donohue, C., Spain, S., Jaeger, E., et al. (2006). Evidence of linkage to chromosome 9q22 33 in colorectal cancer kindreds from the United Kingdom. Cancer res, Vol.66 (10), pp. 5003-5006. show abstract
About 30% of all colorectal cancers are thought to have a genetic basis and the known predisposing genes can only account for a small fraction of cases. A previous report suggested that a colorectal cancer candidate gene, explaining at least 20% of colorectal cancer cases with family history, was located within a 25 cM region on chromosome 9q22.2-q31.3. We typed 16 polymorphic markers encompassing the region of putative linkage in 57 colorectal tumor families from the United Kingdom. Known Mendelian syndromes had been excluded. We found suggestive evidence of linkage, as positive parametric (HLOD = 1.23) and nonparametric (NPL = 1.21, P = 0.11) LOD scores were obtained by analysis of the whole family set. Enrichment for cases with a priori genetic etiology by analyzing families with at least one person affected at < 45 years of age (n = 39 families) gave a maximum multipoint NTL score of 2.65 (P = 0.007). In this group, significant NPL scores > 1.67 (P < 0.05) were found in a 6.5 cM region between D9S1851 and D9S277. With a more stringent threshold (NTL > 2.4, P < 0.01), the linked region was 1.7 cM between D9S971 and D9S272/D9S173. Exclusion from the analysis of kindreds with a phenotype of multiple polyposis also found evidence of linkage in the same region (NPL = 2.47 at close to D9S277, P = 0.009). The type I transforming growth factor-beta receptor, a prime candidate gene, was excluded as a cause of disease. The results presented here further support the existence of a colorectal cancer susceptibility gene on chromosome 9q and refine its likely location..
Kemp, Z., Carvajal-Carmona, L., Spain, S., Barclay, E., Gorman, M., Martin, L., Jaeger, E., Brooks, N., Bishop, D.T., Thomas, H., et al. (2006). Evidence for a colorectal cancer susceptibility locus on chromosome 3q21-q24 from a high-density SNP genome-wide linkage scan (vol 15, pg 2903, 2006). Hum mol genet, Vol.15 (24), pp. 3592-3592.
Hearle, N., Schumacher, V., Menko, F.H., Olschwang, S., Boardman, L.A., Gille, J.J., Keller, J.J., Westerman, A.M., Scott, R.J., Lim, W., et al. (2006). Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin cancer res, Vol.12 (10), pp. 3209-3215. show abstract
BACKGROUND: Although an increased cancer risk in Peutz-Jeghers syndrome is established, data on the spectrum of tumors associated with the disease and the influence of germ-line STK11/LKB1 (serine/threonine kinase) mutation status are limited. EXPERIMENTAL DESIGN: We analyzed the incidence of cancer in 419 individuals with Peutz-Jeghers syndrome, and 297 had documented STK11/LKB1 mutations. RESULTS: Ninety-six cancers were found among individuals with Peutz-Jeghers syndrome. The risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 2%, 5%, 17%, 31%, 60%, and 85%, respectively. The most common cancers represented in this analysis were gastrointestinal in origin, gastroesophageal, small bowel, colorectal, and pancreatic, and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 9%, 15%, and 33%, respectively. In women with Peutz-Jeghers syndrome, the risk of breast cancer was substantially increased, being 8% and 31% at ages 40 and 60 years, respectively. Kaplan-Meier analysis showed that cancer risks were similar in Peutz-Jeghers syndrome patients with identified STK11/LKB1 mutations and those with no detectable mutation (log-rank test of difference chi2 = 0.62; 1 df; P = 0.43). Furthermore, the type or site of STK11/LKB1 mutation did not significantly influence cancer risk. CONCLUSIONS: The results from our study provide quantitative information on the spectrum of cancers and risks of specific cancer types associated with Peutz-Jeghers syndrome..
Rudd, M.F., Sellick, G.S., Webb, E.L., Catovsky, D. & Houlston, R.S. (2006). Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia. Blood, Vol.108 (2), pp. 638-644. show abstract
We conducted a large-scale association study to identify low-penetrance susceptibility alleles for chronic lymphocytic leukemia (CLL), analyzing 992 patients and 2707 healthy controls. To increase the likelihood of identifying disease-causing alleles we genotyped 1467 coding nonsynonymous single nucleotide polymorphisms (nsSNPs) in 865 candidate cancer genes, biasing nsSNP selection toward those predicted to be deleterious. Preeminent associations were identified in SNPs mapping to genes pivotal in the DNA damage-response and cell-cycle pathways, including ATM F858L (odds ratio [OR] = 2.28, P < .0001) and P1054R (OR = 1.68, P = .0006), CHEK2 I157T (OR = 14.83, P = .0008), BRCA2 N372H (OR = 1.45, P = .0032), and BUB1B Q349R (OR = 1.42, P = .0038). Our findings implicate variants in the ATM-BRCA2-CHEK2 DNA damage-response axis with risk of CLL..
Matakidou, A., Eisen, T., Fleischmann, C., Bridle, H., Houlston, R.S. & GELCAPS Consortium, (2006). Evaluation of xeroderma pigmentosum XPA, XPC, XPD, XPF, XPB, XPG and DDB2 genes in familial early-onset lung cancer predisposition. Int j cancer, Vol.119 (4), pp. 964-967. show abstract
Epidemiological data has implicated heterozygosity for xeroderma pigmentosum (XP) as a risk factor for lung cancer. XP has 8 known complementation groups, 7 of which are caused by mutations in genes encoding components of the nucleotide excision repair (NER) pathway. To formally investigate the role of XP-related NER genes in lung cancer susceptibility, we screened germline DNA from 92 familial early-onset lung cancer patients for mutations in all coding regions and intron-exon boundaries of XPA, XPC, XPD, XPF, XPB, XPG and DDB2. Forty-one exonic variants were identified. Twenty-four were nonsynonymous, of which 14 were previously documented polymorphisms. Ten missense variants had not been previously described; none of which were detected in germline DNA from 278 cancer-free controls. Two of the novel missense changes are predicted to be functionally deleterious. Our findings are compatible with XP heterozygosity being a risk factor for lung cancer susceptibility..
Sellick, G.S., Catovsky, D. & Houlston, R.S. (2006). Familial cancer associated with a polymorphism in ARLTS1. N engl j med, Vol.354 (11), pp. 1204-1205.
Matakidou, A., Eisen, T., Bridle, H. & Houlston, R.S. (2006). Nucleotide excision repair polymorphisms modulate overall lung cancer survival and responsiveness to platinum based chemotherapy agents. J clin oncol, Vol.24 (18_suppl), p. 10004. show abstract
10004 Background: The role of DNA repair in maintaining genomic stability and its role in modulating response to chemotherapy agents raises the possibility that variation in these genes may affect lung cancer prognosis. METHODS: To comprehensively evaluate the impact of variation in the nucleotide excision repair (NER) pathway on lung cancer prognosis, we analysed 408 lung cancer patients for all coding, non-synonymous single nucleotide polymorphisms (SNPs) within NER-related genes. RESULTS: Mean age of lung cancer diagnosis among patients was 63 years, 105 patients with small cell lung cancer (SCLC) and 299 with non-small cell lung cancer (NSCLC). The mean follow-up time was 24 months and a total of 234 deaths were observed. Mean survival time was 17.3 and 18.6 months for SCLC and NSCLC respectively. The XPG H1104D minor allele homozygote and the tightly linked CSB M1097V, R1213G, and Q1413R heterozygote genotypes were associated with decreased overall survival, irrespective of whether patients were treated with or without platinum chemotherapy (HRs of 2.22, 95% CI: 1.19-4.16; p=0.013 and 1.39, 95% CI: 1.05-1.84; p=0.02 respectively). No statistically significant interaction was detected between the at-risk genotypes and histology and/or stage of disease at diagnosis. To assess the predictive value of these SNPs in relation to platinum based chemotherapy, genotype-survival associations were evaluated in non-platinum and platinum treated patients. In non-platinum treated patients the RAD23B A249V and CSB M1097V minor allele genotypes were associated with decreased overall survival (p=0.004 and 0.002 respectively), whilst the XPC K939Q minor allele genotype was predictive of improved survival (p=0.03). In platinum-treated patients, carriers of the XPG H1104D minor allele were found to have a statistically significant decrease in their overall survival (p=0.04 and 0.004 for minor allele heterozygote and homozygote patients respectively). CONCLUSIONS: These findings suggest that genetic polymorphisms in the NER genes may modulate overall lung cancer prognosis as well as response to platinum-based chemotherapy agents, independent of histological diagnosis and stage of disease at presentation. No significant financial relationships to disclose..
Webb, E.L., Rudd, M.F. & Houlston, R.S. (2006). Case-control, kin-cohort and meta-analyses provide no support for STK15 F31I as a low penetrance colorectal cancer allele. Br j cancer, Vol.95 (8), pp. 1047-1049. show abstract
Recently, homozygosity for T91A single-nucleotide polymorphism (SNP) in the serine/threonine kinase (STK15) gene, which generates the substitution F31I has been proposed to increase the risk of a number of tumours including colorectal cancer (CRC). To further evaluate the relationship between STK15 F31I and risk of CRC, we genotyped 2558 CRC cases and 2680 controls for this polymorphism. We found no evidence that homozygosity for the STK15 31I genotype confers an increased risk of CRC (odds ratio=0.95, 95% confidence interval (CI): 0.74-1.24). We also conducted a kin-cohort analysis to assess risk among first-degree relatives of the CRC cases. The hazard ratio for I/I homozygotes compared to F/F homozygotes was 1.65 (95% CI: 0.39-3.17). A meta-analysis of our case-control data and three previous studies also provided no evidence of an elevated risk of CRC associated with homozygosity. These data provide no support for the hypothesis that sequence variation in STK15 defined by SNP F31I per se confers an elevated risk of CRC..
Hughes, S., Yoshimoto, M., Beheshti, B., Houlston, R.S., Squire, J.A. & Evans, A. (2006). The use of whole genome amplification to study chromosomal changes in prostate cancer: insights into genome-wide signature of preneoplasia associated with cancer progression. Bmc genomics, Vol.7, p. 65. show abstract
BACKGROUND: Prostate cancer (CaP) is a disease with multifactorial etiology that includes both genetic and environmental components. The knowledge of the genetic basis of CaP has increased over the past years, mainly in the pathways that underlie tumourigenesis, progression and drug resistance. The vast majority of cases of CaP are adenocarcinomas that likely develop through a pre-malignant lesion and high-grade prostatic intraepithelial neoplasia (HPIN). Histologically, CaP is a heterogeneous disease consisting of multiple, discrete foci of invasive carcinoma and HPIN that are commonly interspersed with benign glands and stroma. This admixture with benign tissue can complicate genomic analyses in CaP. Specifically, when DNA is bulk-extracted the genetic information obtained represents an average for all of the cells within the sample. RESULTS: To minimize this problem, we obtained DNA from individual foci of HPIN and CaP by laser capture microdissection (LCM). The small quantities of DNA thus obtained were then amplified by means of multiple-displacement amplification (MDA), for use in genomic DNA array comparative genomic hybridisation (gaCGH). Recurrent chromosome copy number abnormalities (CNAs) were observed in both HPIN and CaP. In HPIN, chromosomal imbalances involving chromosome 8 where common, whilst in CaP additional chromosomal changes involving chromosomes 6, 10, 13 and 16 where also frequently observed. CONCLUSION: An overall increase in chromosomal changes was seen in CaP compared to HPIN, suggesting a universal breakdown in chromosomal stability. The accumulation of CNAs, which occurs during this process is non-random and may indicate chromosomal regions important in tumourigenesis. It is therefore likely that the alterations in copy number are part of a programmed cycle of events that promote tumour development, progression and survival. The combination of LCM, MDA and gaCGH is ideally suited for the identification of CNAs from small cell clusters and may assist in the discovery of potential genomic markers for early diagnosis, or identify the location of tumour suppressor genes (TSG) or oncogenes previously unreported in HPIN and CaP..
Webb, E.L., Sellick, G.S. & Houlston, R.S. (2005). SNPLINK: multipoint linkage analysis of densely distributed SNP data incorporating automated linkage disequilibrium removal. Bioinformatics, Vol.21 (13), pp. 3060-3061. show abstract
SUMMARY: SNPLINK is a Perl script that performs full genome linkage analysis of high-density single nucleotide polymorphism (SNP) marker sets. The presence of linkage disequilibrium (LD) between closely spaced SNP markers can falsely inflate linkage statistics. SNPLINK removes LD from the marker sets in an automated fashion before carrying out linkage analysis. SNPLINK can compute both parametric and non-parametric statistics, utilizing the freely available Allegro and Merlin software. Graphical outputs of whole genome multipoint linkage statistics are provided allowing comparison of results before and after the removal of LD..
Matakidou, A., Eisen, T., Bridle, H., O'Brien, M., Mutch, R. & Houlston, R.S. (2005). Case-control study of familial lung cancer risks in UK women. Int j cancer, Vol.116 (3), pp. 445-450. show abstract
Family history data from a case-control study of lung cancer conducted in the United Kingdom between 1999 and 2004 were analysed to estimate familial risks of the disease. Comparison of lung cancer prevalence in first-degree relatives of 1,482 female lung cancer cases and 1,079 female controls was undertaken using logistic regression adjusting for age and tobacco exposure. Overall, lung cancer in a first-degree relative was associated with a significant increase in the risk of lung cancer [odds ratio (OR) 1.49; 95% confidence interval (CI), 1.13-1.96]. For cases with early onset of the disease (< 60 years), the OR of lung cancer was 2.02 (95% CI, 1.22-3.34). Having 2 or more affected relatives was associated with an OR of 2.68 (95% CI, 1.29-5.55), with a significant trend in risk according to the number of relatives affected (p = 0.001). An increased risk of lung cancer associated with family history of the disease was observed when analysis was restricted to lifetime nonsmokers, although this did not reach significance (OR 1.23; 95% CI, 0.65-2.31). Results confirm previous findings and support the role of a familial predisposition to lung cancer..
Sellick, G.S., Coleman, R.J., Talaban, R.V., Fleischmann, C., Rudd, M.F., Allinson, R., Catovsky, D. & Houlston, R.S. (2005). Germline mutations in Dok1 do not predispose to chronic lymphocytic leukemia. Leuk res, Vol.29 (1), pp. 59-61. show abstract
The genetic basis of familial CLL is poorly understood and to date no gene which when mutated in the germline has been unambiguously shown to confer susceptibility to the disease. Dok1 maps to chromosome 2p13, a region commonly rearranged in CLL. Dok1 inhibits MAP kinase activity, down-regulates cell proliferation and has a suppressive effect on cellular transformation and B-cell signalling pathways. A recent report has implicated mutation of Dok1 in the aetiology of CLL. To examine the proposition that germline mutations in Dok1 act as high penetrance susceptibility alleles for CLL we screened 140 familial cases for functional sequence variants. No pathogenic mutations were detected. This result indicates that germline mutations in Dok1 are unlikely to cause an inherited predisposition to CLL..
Johnson, V., Volikos, E., Halford, S.E., Sadat, E.T., Popat, S., Talbot, I., Truninger, K., Martin, J., Jass, J., Houlston, R., et al. (2005). Exon 3 beta-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome. Gut, Vol.54 (2), pp. 264-267.
Hope, Q., Bullock, S., Evans, C., Meitz, J., Hamel, N., Edwards, S.M., Severi, G., Dearnaley, D., Jhavar, S., Southgate, C., et al. (2005). Macrophage scavenger receptor 1 999C>T (R293X) mutation and risk of prostate cancer. Cancer epidemiol biomarkers prev, Vol.14 (2), pp. 397-402. show abstract
BACKGROUND: Variants in the gene encoding the macrophage scavenger receptor 1 (MSR1(4)) protein have been identified in men with prostate cancer, and several small studies have suggested that the 999C>T (R293X) protein-truncating mutation may be associated with an increased risk for this disease. METHODS: Using large case-control, cohort, and prostate cancer family studies conducted in several Western countries, we tested for the 999C>T mutation in 2,943 men with invasive prostate carcinoma, including 401 males from multiple-case families, 1,982 cases unselected for age, and 575 men diagnosed before the age of 56 years, and in 2,870 male controls. Risk ratios were estimated by unconditional logistic regression adjusting for country and by a modified segregation analysis. A meta-analysis was conducted pooling our data with published data. RESULTS: The prevalence of MSR1*999C>T mutation carriers was 0.027 (SE, 0.003) in cases and 0.022 (SE, 0.002) in controls, and did not differ by country, ethnicity, or source. The adjusted risk ratio for prostate cancer associated with being a 999C>T carrier was 1.31 [95% confidence interval (CI), 0.93-1.84; P = 0.16]. The modified segregation analysis estimated the risk ratio to be 1.20 (95% CI, 0.87-1.66; P = 0.16). The risk ratio estimated from the meta-analysis was 1.34 (95% CI, 0.94-1.89; P = 0.10). CONCLUSION: Our large-scale analysis of case and controls from several countries found no evidence that the 999C>T mutation is associated with increased risk of prostate cancer. The meta-analysis suggests it is unlikely that this mutation confers more than a 2-fold increased risk..
Matakidou, A., Eisen, T. & Houlston, R.S. (2005). Systematic review of the relationship between family history and lung cancer risk. Br j cancer, Vol.93 (7), pp. 825-833. show abstract
We performed a systematic review of 28 case-control, 17 cohort and seven twin studies of the relationship between family history and risk of lung cancer and a meta-analysis of risk estimates. Data from both case-control and cohort studies show a significantly increased lung cancer risk associated with having an affected relative. Risk appears to be greater in relatives of cases diagnosed at a young age and in those with multiple affected family members. Increased lung cancer risk was observed in association with an affected spouse and twin studies, while limited, favour shared environmental exposures. The limitations of the currently published epidemiological studies to infer genetic susceptibility are discussed..
Sellick, G.S., Pritchard-Jones, K., Shepherd, V., Swansbury, J., Catovsky, D. & Houlston, R.S. (2005). Loci other than 21q22 12 (RUNX1) and 16q21-23 2 cause familial AML. Leukemia, Vol.19 (3), pp. 465-466.
Popat, S., Wort, R. & Houlston, R.S. (2005). Relationship between thymidylate synthase (TS) genotype and TS expression: a tissue microarray analysis of colorectal cancers. Int j surg pathol, Vol.13 (2), pp. 127-133. show abstract
Response of colorectal cancers to 5-fluorouracil appears to be influenced by differences in thymidylate synthase (TS) expression. To explore the relationship between TS 5' genotype and expression, we analyzed paired tumor and normal tissue from 87 colorectal cancers by tissue microarray. A trend to an association between TS genotype and expression was observed, but the correlation was weak. Although the 2R homozygote was preferentially associated with TS expression (p<0.03), no relationship was observed for the 3R homozygote (p=1.0). The relationship between 5' TS genotype and TS expression is not simple. For clinical trials incorporating TS status, detection of TS expression in tumors by immunohistochemistry must still remain the benchmark over genotype..
Rasinpera, H., Forsblom, C., Enattah, N.S., Halonen, P., Salo, K., Victorzon, M., Mecklin, J.P., Jarvinen, H., Enholm, S., Sellick, G., et al. (2005). The C/C-13910 genotype of adult-type hypolactasia is associated with an increased risk of colorectal cancer in the Finnish population. Gut, Vol.54 (5), pp. 643-647.
Jefferies, S., Kote-Jarai, Z., Goldgar, D., Houlston, R., Frazer-Williams, M.-., A'Hern, R., Eeles, R., Henk, J., Gore, M., Rhys-Evans, P., et al. (2005). Association between polymorphisms of the GPX1 gene and second primary tumours after index squamous cell cancer of the head and neck. Oral oncol, Vol.41 (5), pp. 455-461. show abstract
We investigated the association between genetic polymorphisms in GPX1 gene amongst patients who had index squamous cell carcinoma (SCCHN) and a second primary tumour (SPT) after a primary SCCHN in a case-control study. GPX1 genotypes were determined for 61 patients with SPT and for 259 control subjects by a PCR technique using a fluorescent-labelled primer. Analysis was by an ABI automated fluorescent sequencer. The associations between specific genotypes and the development of SPT were examined by logistic regression. A significant difference was found between the control group and the SPT cases in allele frequencies of GPX1 ALA( *)6 and ALA( *)7 (p(trend)=0.04). These results suggest that polymorphisms in the GPX1 gene may be a marker for SPT development and further studies are indicated..
Robinson, J.P., Johnson, V.L., Rogers, P.A., Houlston, R.S., Maher, E.R., Bishop, D.T., Evans, D.G., Thomas, H.J., Tomlinson, I.P. & Silver, A.R., et al. (2005). Evidence for an association between compound heterozygosity for germ line mutations in the hemochromatosis (HFE) gene and increased risk of colorectal cancer. Cancer epidemiol biomarkers prev, Vol.14 (6), pp. 1460-1463. show abstract
Whereas a recent study reported an increased risk of colorectal cancer associated with any HFE germ line mutation (C282Y or H63D), other investigators have concluded there is no increased risk, or that any increase is dependent on polymorphisms in HFE-interacting genes such as the transferrin receptor (TFR). We have established the frequency of HFE mutations in colorectal cancer patients (n = 327) with a family history of the disease and randomly selected controls (n = 322); this design increases greatly the study's power. Genotyping for the TRF S142G polymorphism was also conducted on a large proportion of the study group. Using PCR, restriction enzyme mapping, sequencing followed by data analysis with Fisher's exact test and logistic regression, we show that the presence of any HFE mutation (Y282 or D63) was not associated with colorectal cancer risk (P = 0.57). In contrast, individuals compound heterozygous for both mutations (15 cases versus 5 controls) had thrice the odds of developing colorectal cancer (odds ratio, 3.03; 95% confidence interval, 1.06-8.61) compared with those with a single mutation. This finding did not quite reach statistical significance after allowing for multiple post hoc testing (P(observed) = 0.038 versus P = 0.025, with Bonferonni correction). Overall, our data indicate that individuals with a single HFE mutation, C282Y or H63D, are unlikely predisposed to develop colorectal cancer. However, risk of colorectal cancer might be increased by compound heterozygosity for the HFE mutations in the small number of subjects studied. TFR gene polymorphism was not an independent risk factor and did not modify the disease risk associated with HFE mutation..
Jønsson, V., Houlston, R.S., Catovsky, D., Yuille, M.R., Hilden, J., Olsen, J.H., Fajber, M., Brandt, B., Sellick, G., Allinson, R., et al. (2005). CLL family 'Pedigree 14' revisited: 1947-2004. Leukemia, Vol.19 (6), pp. 1025-1028. show abstract
The notion that inherited predisposition contributes to the development of haematological malignancies is generally thought of as being a relatively new idea. However, Videbaek made a clear enunciation of such a hypothesis in 1947, from a study of tumour incidence in relatives of patients with different leukaemias. To gain further insight into inherited susceptibility to chronic lymphocytic leukaemia (CLL), we followed up the descendants of Videbaek's 'Pedigree 14' series of families. Using the Danish medical and pedigree databases, complete tracing of 222 descendants of the original 57 family members was achieved. To date, 10 family members have been diagnosed with CLL, one with T-cell lymphoma and 17 with nonhaematological cancers, including five with breast cancer. The detailed follow up of this family provides further support for inherited predisposition to CLL and illustrates the value of follow-up studies of previously published family material for genetic analyses..
Sellick, G.S., Longman, C., Brockington, M., Mahjneh, I., Sagi, L., Bushby, K., Topaloğlu, H., Muntoni, F. & Houlston, R.S. (2005). Localisation of merosin-positive congenital muscular dystrophy to chromosome 4p16 3. Hum genet, Vol.117 (2-3), pp. 207-212. show abstract
The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders, which present within the first 6 months of life with hypotonia, muscle weakness and contractures, associated with dystrophic changes on skeletal muscle biopsy. We have previously reported a large consanguineous family segregating merosin-positive congenital muscular dystrophy, in which involvement of known CMD loci was excluded. A genome-wide linkage search of the family conducted using microsatellite markers spaced at 10-Mb intervals failed to identify a disease locus. A second scan using a high-density SNP array, however, permitted a novel CMD locus on 4p16.3 to be identified (multipoint LOD score 3.4). Four additional consanguineous CMD families with a similar phenotype were evaluated for linkage to a 4.14-Mb interval on 4p16.3; however, none showed any evidence of linkage to the region. Our findings further illustrate the utility of highly informative SNP arrays compared with standard panels of microsatellite markers for the mapping of recessive disease loci..
Sellick, G.S., Spendlove, H.E., Catovsky, D., Pritchard-Jones, K. & Houlston, R.S. (2005). Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia. Leukemia, Vol.19 (7), pp. 1276-1278.
Matakidou, A. & Houlston, R. (2005). David N Cooper (ed) The molecular genetics of lung cancer (2005) Springer, ISBN 3-540-22985-X, hardcover, €106 99. Hum genet, Vol.117 (4), p. 410.
Marti, G.E., Rawstron, A.C., Ghia, P., Hillmen, P., Houlston, R.S., Kay, N., Schleinitz, T.A., Caporaso, N. & International Familial CLL Consortium, (2005). Diagnostic criteria for monoclonal B-cell lymphocytosis. Br j haematol, Vol.130 (3), pp. 325-332. show abstract
Very low levels of circulating monoclonal B-cell subpopulations can now be detected in apparently healthy individuals using flow cytometry. We propose the term 'monoclonal B-cell lymphocytosis' (MBL) to describe this finding. The aim of this document is to provide a working definition of MBL for future clinical, epidemiological and laboratory studies. We propose that the detection of a monoclonal B-cell population by light chain restriction is sufficient to define this condition in individuals not meeting the diagnostic criteria for other B-lymphoproliferative disorders. The majority of individuals with MBL will have cells that are indistinguishable from chronic lymphocytic leukaemia (CLL). However, this blood cell clonal expansion of CD5+ or CD5- B-lymphocytes is age-dependent and immunophenotypic heterogeneity is common. Longitudinal studies are required to determine whether MBL is a precursor state to CLL or other B-lymphoproliferative disease in a situation analogous to a monoclonal gammopathy of undetermined significance and myeloma. Future studies of MBL should be directed towards determining its relationship to clinical disease, particularly in individuals from families with a genetic predisposition to developing CLL..
Marti, G.E., Rawstron, A.C., Ghia, P., Hillmen, P., Houlston, R.S., Kay, N., Schleinitz, T.A. & Caporaso, N. (2005). MBL and MoBL - Response. Brit j haematol, Vol.130 (5), pp. 795-796.
Popat, S. & Houlston, R.S. (2005). A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis. Eur j cancer, Vol.41 (14), pp. 2060-2070. show abstract
Results from studies investigating the relationship between colorectal cancer survival and chromosome 18q allelic imbalance (AI)/loss of DCC expression (LOE) have been inconsistent. We have reviewed and pooled published studies to estimate the prognostic significance of chromosome 18q status more precisely. Data from 27 studies were eligible. Survival data were pooled using standard meta-analysis techniques. Considerable variation between assessment method, marker choice, and threshold for assigning AI/LOE was observed. Pooling data from a 2189 cases from 17 studies showed significantly worse overall survival in patients with AI/LOE (HR = 2.00, 95%CI: 1.49-2.69), maintained both in the adjuvant setting (HR = 1.69, 95%CI:1.13-2.54), and also by method (HR = 1.67, 95%CI: 1.19-2.36, genotyping microsatellites; HR = 3.00, 95%CI: 1.98-4.56, immunohistochemistry). There was however evidence of heterogeneity and publication bias. Cancers with chromosome 18q loss appear to have a poorer prognosis. Prospective studies using consistent methodology are needed to precisely quantify its effect and role in patients with stage II-III disease..
Sellick, G.S., Webb, E.L., Allinson, R., Matutes, E., Dyer, M.J., Jonsson, V., Langerak, A.W., Mauro, F.R., Fuller, S., Wiley, J., et al. (2005). A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci. Am j hum genet, Vol.77 (3), pp. 420-429. show abstract
Chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders (LPDs) show clear evidence of familial aggregation, but the inherited basis is largely unknown. To identify a susceptibility gene for CLL, we conducted a genomewide linkage analysis of 115 pedigrees, using a high-density single-nucleotide polymorphism (SNP) array containing 11,560 markers. Multipoint linkage analyses were undertaken using both nonparametric (model-free) and parametric (model-based) methods. Our results confirm that the presence of high linkage disequilibrium (LD) between SNP markers can lead to inflated nonparametric linkage (NPL) and LOD scores. After the removal of high-LD SNPs, we obtained a maximum NPL of 3.14 (P=.0008) on chromosome 11p11. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under both dominant (HLOD 1.95) and recessive (HLOD 2.78) models. In addition, four other chromosomal positions (5q22-23, 6p22, 10q25, and 14q32) displayed HLOD scores >1.15 (which corresponds to a nominal P value <.01). None of the regions coincided with areas of common chromosomal abnormalities frequently observed for CLL. These findings strengthen the argument for an inherited predisposition to CLL and related B-cell LPDs..
Sellick, G.S., Coleman, R.J., Webb, E.L., Chow, J., Bevan, S., Rosbotham, J.L. & Houlston, R.S. (2005). Dominantly inherited cutaneous small-vessel lymphocytic vasculitis maps to chromosome 6q26-q27. Hum genet, Vol.118 (1), pp. 82-86. show abstract
Outside the context of hereditary deficiencies of complement and IgA, Mendelian inherited predisposition to small vessel lymphocytic vasculitis (SVLV) has rarely been documented. Here we report a large, multigenerational family segregating symmetrical cutaneous SVLV affecting the cheeks, thighs and hands. In all affected family members the disease presented in early infancy and there was no evidence for an association with systemic disease. Skin biopsy of lesions showed a lymphocytic vasculitis with red blood cell extravasation. Complementary studies, with extensive investigation focused on dysfunction of the immunological system were negative. The pattern of inheritance of SVLV in the family was compatible with an autosomal dominantly acting disease gene with incomplete penetrance. To localize the disease causing gene in the family a genome-wide linkage search was conducted using a high-density SNP array. Haplotype construction and analysis of recombination events permitted the minimal interval defining the disease locus to be refined to a 4.7 Mb region on chromosome 6q26-q27. The genes CCR6 and GPR31, which map to the linked region represent plausible candidates for the disease on the basis of their biological function. Extensive screening of both genes by mutational analysis failed to identify a deleterious mutation in the family..
Rudd, M.F., Williams, R.D., Webb, E.L., Schmidt, S., Sellick, G.S. & Houlston, R.S. (2005). The predicted impact of coding single nucleotide polymorphisms database. Cancer epidemiol biomarkers prev, Vol.14 (11 Pt 1), pp. 2598-2604. show abstract
Nonsynonymous single nucleotide polymorphisms (nsSNP) have the potential to affect the structure or function of expressed proteins and are, therefore, likely to represent modifiers of inherited susceptibility. We have classified and catalogued the predicted functionality of nsSNPs in genes relevant to the biology of cancer to facilitate sequence-based association studies. Candidate genes were identified using targeted search terms and pathways to interrogate the Gene Ontology Consortium database, Kyoto Encyclopedia of Genes and Genomes database, Iobion's Interaction Explorer PathwayAssist Program, National Center for Biotechnology Information Entrez Gene database, and CancerGene database. A total of 9,537 validated nsSNPs located within annotated genes were retrieved from National Center for Biotechnology Information dbSNP Build 123. Filtering this list and linking it to 7,080 candidate genes yielded 3,666 validated nsSNPs with minor allele frequencies > or =0.01 in Caucasian populations. The functional effect of nsSNPs in genes with a single mRNA transcript was predicted using three computational tools-Grantham matrix, Polymorphism Phenotyping, and Sorting Intolerant from Tolerant algorithms. The resultant pool of 3,009 fully annotated nsSNPs is accessible from the Predicted Impact of Coding SNPs database at http://www.icr.ac.uk/cancgen/molgen/MolPopGen_PICS_database.htm. Predicted Impact of Coding SNPs is an ongoing project that will continue to curate and release data on the putative functionality of coding SNPs..
McIntyre, A., Summersgill, B., Spendlove, H.E., Huddart, R., Houlston, R. & Shipley, J. (2005). Activating mutations and/or expression levels of tyrosine kinase receptors GRB7, RAS, and BRAF in testicular germ cell tumors. Neoplasia, Vol.7 (12), pp. 1047-1052. show abstract
Amplification and/or overexpression of genes encoding tyrosine kinase receptors KIT and ERBB2 have been reported in testicular germ cell tumors (TGCTs). These receptors can bind the adaptor molecule GRB7 encoded by a gene adjacent to ERBB2 at 17q12, a region also frequently gained in TGCTs. GRB7 binding may be involved in the activation of RAS signaling and KRAS2 maps to 12p, which is constitutively gained in TGCT and lies within a minimum overlapping region of amplification at 12p11.2-12.1, a region we have previously defined. RAS proteins activate BRAF, and activating mutations of genes encoding these proteins have been described in various tumors. Here we determine the relationships between expression levels and activating mutations of these genes in a series of 65 primary TGCTs and 4 TCGT cell lines. High levels of expression and activating mutations in RAS were mutually exclusive events, and activating mutations in RAS were only identified in the seminoma subtype. Mutations in BRAF were not identified. Increased ERBB2 expression was associated with differentiated nonseminoma histology excised from lymph nodes postchemotherapy. Mutation, elevated expression, and correlations between expression levels of KRAS2, GRB7, and KIT are consistent with their involvement in the development of TGCTs..
Hughes, S., Damato, B.E., Giddings, I., Hiscott, P.S., Humphreys, J. & Houlston, R.S. (2005). Microarray comparative genomic hybridisation analysis of intraocular uveal melanomas identifies distinctive imbalances associated with loss of chromosome 3. Br j cancer, Vol.93 (10), pp. 1191-1196. show abstract
Defining regions of genomic imbalance can identify genes involved in tumour development. Conventional cytogenetics has identified several nonrandom copy number alterations (CNA) in uveal melanomas (UVM), which include monosomy 3, chromosome 6 abnormalities and gain of 8q. To gain further insight into the CNAs and define the regions involved more precisely we analysed 18 primary UVMs using 1 Mb BAC microarray comparative genomic hybridisation (CGH). Our analysis showed that the most common genomic imbalances were 8q gain (78%), 6p gain (67%) and monosomy 3 (56%). Two distinct CGH profiles could be delineated on the basis of the chromosome 3 status. The most common genetic changes in monosomy 3 tumours, in our study, were gain of 8q11.21-q24.3, 6p25.1-p21.2, 21q21.2-q21.3 and 21q22.13-q22.3 and loss of 1p36.33-p34.3, 1p31.1-p21.2, 6q16.2-q25.3 and 8p23.3-p11.23. In contrast, disomy 3 tumours showed recurrent gains of only 6p25.3-p22.3 and 8q23.2-q24.3. Our approach allowed definition of the smallest overlapping regions of imbalance, which may be important in the development of UVM..
Hearle, N.C., Tomlinson, I., Lim, W., Murday, V., Swarbrick, E., Lim, G., Phillips, R., Lee, P., O'Donohue, J., Trembath, R.C., et al. (2005). Sequence changes in predicted promoter elements of STK11/LKB1 are unlikely to contribute to Peutz-Jeghers syndrome. Bmc genomics, Vol.6, p. 38. show abstract
BACKGROUND: Germline mutations or large-scale deletions in the coding region and splice sites of STK11/LKB1 do not account for all cases of Peutz-Jeghers syndrome (PJS). It is conceivable that, on the basis of data from other diseases, inherited variation in promoter elements of STK11/LKB1 may cause PJS. RESULTS: Phylogenetic foot printing and transcription factor binding site prediction of sequence 5' to the coding sequence of STK11/LKB1 was performed to identify non-coding sequences of DNA indicative of regulatory elements. A series of 33 PJS cases in whom no mutation in STK11/LKB1 could be identified were screened for sequence changes in the putative promoter defined by nucleotides -1090 to -1472. Two novel sequence changes were identified, but were found to be present in healthy individuals. CONCLUSION: These findings indicate that promoter sequence changes are unlikely to contribute to PJS..
Popat, S., Matakidou, A. & Houlston, R.S. (2005). Thymidylate synthase expression in colorectal cancer: The never-ending story - In reply. J clin oncol, Vol.23 (9), pp. 2108-2109.
Popat, S., Hubner, R. & Houlston, R.S. (2005). Systematic review of microsatellite instability and colorectal cancer prognosis. J clin oncol, Vol.23 (3), pp. 609-618. show abstract
Purpose A number of studies have investigated the relationship between microsatellite instability (MSI) and colorectal cancer (CRC) prognosis. Although many have reported a better survival with MSI, estimates of the hazard ratio (HR) among studies differ. To derive a more precise estimate of the prognostic significance of MSI, we have reviewed and pooled data from published studies.Methods Studies stratifying survival in CRC patients by MSI status were eligible for analysis. The principal outcome measure was the HR. Data from eligible studies were pooled using standard techniques.Results Thirty-two eligible studies reported survival in a total of 7,642 cases, including 1,277 with MSI. There was no evidence of publication bias. The combined HR estimate for overall survival associated with MSI was 0.65 (95% Cl, 0.59 to 0.71; heterogeneity P = .16; I-2 = 20%). This benefit was maintained restricting analyses to clinical trial patients (HR = 0.69; 95% Cl, 0.56 to 0.85) and patients with locally advanced CRC (HR = 0.67; 95% Cl, 0.58 to 0.78). In patients treated with adjuvant fluorouracil (FU) CRCs with MSI had a better prognosis (HR = 0.72; 95% Cl, 0.61 to 0.84). However, while data are limited, tumors with MSI derived no benefit from adjuvant FU (HR = 1.24; 95% Cl, 0.72 to 2.14).Conclusion CRCs with MSI have a significantly better prognosis compared to those with intact mismatch repair. Additional studies are needed to further define the benefit of adjuvant chemotherapy in locally advanced tumors with MSI. (C) 2005 by American Society of Clinical Oncology..
PURPOSE: A number of studies have investigated the relationship between microsatellite instability (MSI) and colorectal cancer (CRC) prognosis. Although many have reported a better survival with MSI, estimates of the hazard ratio (HR) among studies differ. To derive a more precise estimate of the prognostic significance of MSI, we have reviewed and pooled data from published studies. METHODS: Studies stratifying survival in CRC patients by MSI status were eligible for analysis. The principal outcome measure was the HR. Data from eligible studies were pooled using standard techniques. RESULTS: Thirty-two eligible studies reported survival in a total of 7,642 cases, including 1,277 with MSI. There was no evidence of publication bias. The combined HR estimate for overall survival associated with MSI was 0.65 (95% CI, 0.59 to 0.71; heterogeneity P = .16; I(2) = 20%). This benefit was maintained restricting analyses to clinical trial patients (HR = 0.69; 95% CI, 0.56 to 0.85) and patients with locally advanced CRC (HR = 0.67; 95% CI, 0.58 to 0.78). In patients treated with adjuvant fluorouracil (FU) CRCs with MSI had a better prognosis (HR = 0.72; 95% CI, 0.61 to 0.84). However, while data are limited, tumors with MSI derived no benefit from adjuvant FU (HR = 1.24; 95% CI, 0.72 to 2.14). CONCLUSION: CRCs with MSI have a significantly better prognosis compared to those with intact mismatch repair. Additional studies are needed to further define the benefit of adjuvant chemotherapy in locally advanced tumors with MSI..
Popat, S. & Houlston, R.S. (2005). Re: Reporting recommendations for tumor marker prognostic studies (REMARK). J natl cancer inst, Vol.97 (24), p. 1855.
Forrest, M.S., Edwards, S.M., Houlston, R., Kote-Jarai, Z., Key, T., Allen, N., Knowles, M.A., Turner, F., Ardern-Jones, A., Murkin, A., et al. (2005). Association between hormonal genetic polymorphisms and early-onset prostate cancer. Prostate cancer prostatic dis, Vol.8 (1), pp. 95-102. show abstract
We investigated the association between seven polymorphisms in four candidate genes involved in vitamin D and androgen metabolism with early-onset prostate cancer (CaP) risk. The polymorphisms were genotyped in 288 UK males who were diagnosed with CaP at the age of 55 y or younger and up to 700 population-based controls. An additional 50 cases (not selected for age) and 76 controls were also genotyped. Short (< or =22 repeats) AR (CAG)(n) repeats were associated with a significantly reduced risk of early onset CaP (OR 0.68, 95% CI 0.50-0.91) compared with men with long (> 22) repeats. Men homozygous for the leucine variant of SRD5A2 p.89V > L were also found to be at a significantly increased risk of CaP compared with men who were homozygous for the valine allele (OR 1.84, 95% CI 1.15-2.98). No associations were found with the AR (GGC)(n), CYP17 Msp A1 I, VDR Taq I, SRD5A2 (TA)(n) and p.49A >T polymorphisms and CaP risk. These findings suggest that common polymorphisms in the AR and SRD5A2 genes may be associated with early-onset CaP in British men..
Talaban, R., Sellick, G.S., Spendlove, H.E., Howell, R., King, C., Reckless, J., Newbury-Ecob, R. & Houlston, R.S. (2005). Inherited pericentric inversion (X)(p11 4q11 2) associated with delayed puberty and obesity in two brothers. Cytogenet genome re