***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Genome-wide DNA hypomethylation plays has an important role in genomic instability and colorectal carcinogenesis . However , the relationship between cellular DNA methylation level and patient outcome remains uncertain . Using 643 colon cancers in two independent prospect i ve cohorts , we quantified DNA methylation in repetitive long interspersed nucleotide element-1 ( LINE-1 ) elements using pyrosequencing , which is a good indicator of global DNA methylation level . We used Cox proportional hazard models to calculate hazard ratios ( HRs ) of colon cancer-specific and overall mortality , adjusting for patient and tumoral features , including CpG isl and methylator phenotype ( CIMP ) . Statistical tests were two-sided . LINE-1 hypomethylation was linearly associated with a statistically significant increase in colon cancer-specific mortality ( for a 30 % decrease in LINE-1 methylation : multivariable HR = 2.37 , 95 % confidence interval [ CI ] = 1.42 to 3.94 ; P(trend ) < .001 ) and overall mortality ( multivariable HR = 1.85 , 95 % CI = 1.25 to 2.75 ; P(trend ) = .002 ) . The association was consistent across the two independent cohorts and strata of clinical and molecular characteristics , including sex , age , tumor location , stage , and CIMP , microsatellite instability , KRAS , BRAF , p53 , and chromosomal instability status . In conclusion , tumoral LINE-1 hypomethylation is independently associated with shorter survival among colon cancer patients Background Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis . LINE-1 ( L1 retrotransposon ) constitutes a substantial portion of the human genome , and LINE-1 methylation correlates with global DNA methylation status . LINE-1 hypomethylation in colon cancer has been strongly associated with poor prognosis . However , whether LINE-1 hypomethylators constitute a distinct cancer subtype remains uncertain . Recent evidence for concordant LINE-1 hypomethylation within synchronous colorectal cancer pairs suggests the presence of a non-stochastic mechanism influencing tumor LINE-1 methylation level . Thus , it is of particular interest to examine whether its wide variation can be attributed to clinical , pathologic or molecular features . Design Utilizing a data base of 869 colorectal cancers in two prospect i ve cohort studies , we constructed multivariate linear and logistic regression models for LINE-1 methylation ( quantified by Pyrosequencing ) . Variables included age , sex , body mass index , family history of colorectal cancer , smoking status , tumor location , stage , grade , mucinous component , signet ring cells , tumor infiltrating lymphocytes , CpG isl and methylator phenotype ( CIMP ) , microsatellite instability , expression of TP53 ( p53 ) , CDKN1A ( p21 ) , CTNNB1 ( β-catenin ) , PTGS2 ( cyclooxygenase-2 ) , and FASN , and mutations in KRAS , BRAF , and PIK3CA . Results Tumoral LINE-1 methylation ranged from 23.1 to 90.3 of 0 - 100 scale ( mean 61.4 ; median 62.3 ; st and ard deviation 9.6 ) , and distributed approximately normally except for extreme hypomethylators [ LINE-1 methylation < 40 ; N = 22 ( 2.5 % ) , which were far more than what could be expected by normal distribution ] . LINE-1 extreme hypomethylators were significantly associated with younger patients ( p = 0.0058 ) . Residual plot by multivariate linear regression showed that LINE-1 extreme hypomethylators clustered as one distinct group , separate from the main tumor group . The multivariate linear regression model could explain 8.4 % of the total variability of LINE-1 methylation ( R-square = 0.084 ) . Multivariate logistic regression models for binary LINE-1 hypomethylation outcomes ( cutoffs of 40 , 50 and 60 ) showed at most fair predictive ability ( area under receiver operator characteristics curve < 0.63 ) . Conclusions LINE-1 extreme hypomethylators appear to constitute a previously-unrecognized , distinct subtype of colorectal cancers , which needs to be confirmed by additional studies . Our tumor LINE-1 methylation data indicate enormous epigenomic diversity of individual colorectal cancers Background : Recent data suggest a link between blood leukocyte DNA methylation , and cancer risk . However , reports on DNA methylation from a prospect i ve study are unavailable for gastric cancer . Methods : We explored the association between methylation in  pre-diagnostic blood leukocyte DNA and gastric cancer risk in a case – control study nested in the prospect i ve Shanghai Women 's Health Study cohort . Incident gastric cancer cases ( n=192 ) and matched controls ( n=384 ) were included in the study .  Methylation of Alu and long interspersed nucleotide elements (LINE)-1 were evaluated using bisulphite pyrosequencing .  Odds ratios ( ORs ) and 95 % confidence intervals ( CI ) were calculated from logistic regression adjusting for potential confounders . Results : Alu methylation was inversely associated with gastric cancer risk , mainly among cases diagnosed one or more years after blood collection . After excluding cases diagnosed during the first year of follow-up , the ORs for the third , second , and first quartiles of Alu methylation compared with the highest quartile were 2.43 ( 1.43–4.13 ) , 1.47(0.85–2.57 ) , and 2.22 ( 1.28–3.84 ) , respectively . This association appeared to be modified by dietary intake , particularly isoflavone . In contrast , LINE-1 methylation levels were not associated with gastric cancer risk . Conclusion : Evidence from this prospect i ve study is consistent with the hypothesis that DNA hypomethylation in blood leukocytes may be related to cancer risk , including risk of gastric cancer Background : Many groups are actively investigating how the epigenetic state relates to environmental exposures and development of disease , including cancer . There are myriad choices for capturing and measuring the epigenetic state of a tissue , ranging from assessing the total methyl-CpG content to array-based platforms that simultaneously probe hundreds of thous and s of CpG loci . There is an emerging literature that uses CpG methylation at repetitive sequences , including LINE-1 ( long interspersed nuclear element-1 ) elements , to capture the epigenomic state . Objectives : We explored the complexity of using CpG methylation at repetitive sequences in epidemiology and translational medical research and suggest needed avenues of research to clarify its meaning and utility . Conclusions : Among the most urgent avenues of research is the need for prospect i ve studies to eliminate the possibilities of reverse causality , and development of new LINE-1 assays that capture both class of LINE-1 element and copy number Global DNA hypomethylation is associated with genomic instability and human cancer and blood DNAs collected at the time of cancer diagnosis have been used to examine the relationship between global methylation and cancer risk . To test the hypothesis that global hypomethylation is associated with increased risk of hepatocellular carcinoma ( HCC ) , we conducted a prospect i ve case-control study nested within a community-based cohort with 16 years of follow-up . We measured methylation levels in Satellite 2 ( Sat2 )  by MethyLight and LINE-1 by pyrosequencing using baseline white blood cell DNA from 305 HCC cases and 1254 matched controls . We found that Sat2 hypomethylation was associated with HCC risk [ odds ratio ( OR ) per unit decrease in natural log Sat2 methylation = 1.77 , 95 % confidence interval ( CI ) = 1.06 - 2.95 ] . The association was significant among individuals diagnosed with HCC before age 62 ( OR per unit decrease in natural log Sat2 methylation = 2.47 , 95 % CI = 1.06 - 5.73 ) but not after ( OR = 1.67 , 95 % CI = 0.84 - 3.32 ) . We did not observe an association of LINE-1 with HCC overall risk by age at diagnosis . Among carriers of hepatitis B virus surface antigen ( HBsAg ) , with each 1U decrease in natural log Sat2 methylation level , the OR for HCC increased by 2.19 ( 95 % CI = 1.00 - 4.89 ) . LINE-1 hypomethylation was associated with about a 2-fold increased risk of HCC , with ORs ( 95 % CI ) of 2.39 ( 1.06 - 5.39 ) , 2.09 ( 0.91 - 4.77 ) and 2.28 ( 0.95 - 5.51 , P(trend ) = 0.14 ) for HBsAg carriers in the third , second and lowest quartile of LINE-1 methylation , respectively compared with carriers in the fourth . These results suggest that global hypomethylation may be a useful biomarker of HCC susceptibility Purpose : This study aims to quantitatively assess promoter and global methylation changes in pheochromocytomas and abdominal paragangliomas and its relation to tumor phenotypes . Experimental Design : A panel of 53 primary tumors ( 42 benign , 11 malignant ) was analyzed by quantitative bisulfite pyrosequencing . Based on methylation levels in the tumor suppressor genes , p16INK4A , CDH1 , DCR2 , RARB , RASSF1A , NORE1A , TP73 , APC , DAPK1 , p14ARF , and PTEN , a CpG isl and methylator phenotype ( CIMP ) was defined as concerted hypermethylation in three or more genes . Mean Z scores for the hypermethylated promoters were calculated to characterize overall promoter methylation . Global DNA methylation was quantified for LINE-1 promoter sequences and by using luminescent methylation analysis . Results : Five primary tumors ( 9.4 % ) exhibited a CIMP phenotype , four of which were malignant paragangliomas . CIMP was significantly associated with malignant behavior ( P = 0.005 ) and younger age at presentation ( P < 0.007 ) but did not result from BRAF V600E mutation . Global hypomethylation of LINE-1 elements was observed in tumors compared with normal adrenal sample s ( P < 0.02 ) . Conclusion : We here describe the identification of CIMP in abdominal paragangliomas and a strong association of this phenotype with malignant behavior , as well as young age at presentation . The findings raise a prospect i ve for potential benefits of epigenetically acting drugs for a subgroup of young abdominal paraganglioma patients with adverse prognosis 
    Output:
    
The present meta- analysis adds new evidence to the growing literature on the role of LINE-1 hypomethylation in human cancer and demonstrates that LINE-1 methylation levels were significantly lower in cancer patients than in control sample s , especially in certain cancer types .
This result was confirmed in tissue sample s , both fresh/frozen or FFPE specimens , but not in blood .