***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: PURPOSE To identify single nucleotide polymorphisms ( SNPs ) associated with development of  erectile dysfunction ( ED ) among prostate cancer patients treated with radiation therapy .  METHODS AND MATERIAL S A 2-stage genome-wide association study was performed . Patients were split r and omly into a stage I discovery cohort ( 132 cases , 103 controls ) and a stage II replication cohort ( 128 cases , 102 controls ) . The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays . The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays . RESULTS Twelve SNPs identified in the discovery cohort and vali date d in the replication cohort were associated with development of ED following radiation therapy ( Fisher combined P values 2.1 × 10(-5 ) to 6.2 × 10(-4 ) ) . Notably , these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions ( adhesion and signaling ) rather than DNA damage repair . In a multivariable model including nongenetic risk factors , the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort . There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status ( Sommers ' D P value=1.7 × 10(-29 ) ) . A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 ( P value=2.1 × 10(-19 ) ) . The cumulative SNP score model had a sensitivity of 84 % and specificity of 75 % for prediction of developing ED at the radiation therapy planning stage . CONCLUSIONS This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy . These c and i date genetic predictors warrant more definitive validation in an independent cohort There is increasing evidence supporting the role of genetic variants in the development of radiation-induced toxicity . However , previous c and i date gene association studies failed to eluci date the common genetic variation underlying this phenotype , which could emerge years after the completion of treatment . We performed a genome-wide association study on a Spanish cohort of 741 individuals with prostate cancer treated with external beam radiotherapy ( EBRT ) . The replication cohorts consisted of 633 cases from the UK and 368 cases from North America . One locus comprising TANC1 ( lowest unadjusted P value for overall late toxicity = 6.85 × 10−9 , odds ratio ( OR ) = 6.61 , 95 % confidence interval ( CI ) = 2.23–19.63 ) was replicated in the second stage ( lowest unadjusted P value for overall late toxicity = 2.08 × 10−4 , OR = 6.17 , 95 % CI = 2.25–16.95 ; Pcombined = 4.16 × 10−10 ) . The inclusion of the third cohort gave unadjusted Pcombined = 4.64 × 10−11 . These results , together with the role of TANC1 in regenerating damaged muscle , suggest that the TANC1 locus influences the development of late radiation-induced damage Purpose Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual . Our objective was to evaluate the association between single-nucleotide polymorphisms ( SNPs ) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy .  Methods In a multicenter clinical trial ( E1201 ) , 81 eligible treatment-naïve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy , with planned subsequent surgical resection .  Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy , occurring during or up to 6 weeks following the completion of radiochemotherapy . SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double str and ed break repair , or platinum influx , efflux , or detoxification . Results Grade ≥3 radiation-related toxicity ( mostly dysphagia ) and myelosuppression occurred in 18 and 33 % of subjects , respectively . The variant alleles of the XRCC2 5′ flanking SNP ( detected in 28 % of subjects ) and of GST-Pi Ile-105-Val ( detected in 65 % of subjects ) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote ( 47 % vs. 9 % , and 31 % vs. 0 % , respectively ; P = 0.005 ) . No SNP was associated with myelosuppression . Conclusions This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity PURPOSE Clinical radiosensitivity varies considerably among patients , and radiation-induced side effects developing in normal tissue can be therapy limiting . Some single nucleotide polymorphisms ( SNPs ) have been shown to correlate with hypersensitivity to radiotherapy . We conducted a prospect i ve study of 87 female patients with breast cancer who received radiotherapy after breast surgery . We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes : XRCC1 ( Arg399Gln and Arg194Trp ) , XRCC3 ( Thr241Met ) , XPD ( Asp312Asn and Lys751Gln ) , MSH2 ( gIVS12 - 6T > C ) , MLH1 ( Ile219Val ) , MSH3 ( Ala1045Thr ) , MGMT ( Leu84Phe ) , and in damage-detoxification GSTM1 and GSTT1 genes ( allele deletion ) . METHODS AND MATERIAL S Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms . The development of severe acute skin reaction ( moist desquamation or interruption of radiotherapy due to toxicity ) associated with genetic polymorphisms was modeled using Cox proportional hazards , accounting for cumulative biologically effective radiation dose . RESULTS Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3 - 241Met allele ( hazard ratio [ HR ] unquantifiably high ) , MSH2 gIVS12 - 6nt-C allele ( HR=53.36 ; 95 % confidence intervals [ 95 % CI ] , 3.56 - 798.98 ) , and MSH3 - 1045Ala allele ( HR unquantifiably high ) . Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity ( HR=38.26 ; 95 % CI , 1.19 - 1232.52 ) . CONCLUSIONS To our knowledge , this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients . Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy . Genetic polymorphisms may be promising c and i date s for predicting acute radiosensitivity , but further studies are necessary to confirm our findings Purpose : Several DNA repair gene polymorphisms have been described , which affect DNA repair capacity and modulate cancer susceptibility . We evaluated the association of six polymorphisms in the DNA repair genes : XRCC1 ( Arg194Trp , Arg280His , and Arg399Gln ) , APE1 ( Asp148Glu ) , and XPD ( Lys751Gln and Asp312Asn ) , with the risk of acute skin reactions following radiotherapy . Design : We conducted a prospect i ve study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery .  Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes . The development of acute skin reactions ( moist desquamation ) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards , accounting for cumulative biologically effective radiation dose . Results : Overall , the development of acute toxicity , which presented in 77 patients , was not associated with the genetic variants studied , although the hazard ratios ( HR ) were generally below 1 . Risks were however differential by body mass index . Among normal-weight patients only , both carriers of the APE1 148Glu and the XRCC1 399Gln alleles had decreased risk of acute skin reactions after radiotherapy ( HR , 0.49 and 0.51 , respectively ) . The results for XRCC1 were confirmed by haplotype analysis . When considering joint effects , we observed that compared with homozygote carriers of the wild-type allele in both genes , the risk was most strongly reduced in carriers of both APE1 148Glu and XRCC1 399Gln alleles with normal weight [ HR , 0.19 ; 95 % confidence interval ( 95 % CI ) , 0.06 - 0.56 ] but not in those with overweight ( HR , 1.39 ; 95 % CI , 0.56 - 3.45 ; Pinteraction = 0.009 ) . Conclusion : The XRCC1 399Gln or APE1 148Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight Radiotherapy is associated with a board spectrum of early and late normal tissue injury . It is a basic clinical observation that even within a group of identically treated patients large variability exists in the incidence and severity of radiation sequelae . Although this is partly a result of the r and om nature of radiation-induced cell killing , there are at least two additional phenomena involved . One is that certain cofactors influence the expression of radiation damage . These include for example , age of the patient , hemoglobin level , and smoking habits . Another type of predisposing factors are related to coexisting morbidity , like collagen vascular disease , diabetes mellitus , hypertension , and infections . The influence of these factors on the expression of normal tissue injury is critically review ed and some of the method ological problems involved in this field are discussed . The other phenomenon , that probably contributes to the patient-to-patient variability in the expression of normal tissue reactions , is the variability in intrinsic cellular radiosensitivity that has been shown among individuals . Clinical studies have shown that patients who express a given type of normal tissue injury in one treated area are more likely also to express this injury in another treated area . On the other h and , different normal tissue reactions seem to have a very limited , if any , intrapatient correlation . A number of genetic syndromes are associated with hypersensitivity to radiation , both clinical ly and in vitro . Also , studies have shown that highly selected patients who express an unusually strong response to radiotherapy , are likely to have in vitro radiosensitivities in the lower normal range . Recently , two studies on otherwise unselected patients support the hypothesis that in vitro radiosensitivity of normal human skin fibroblasts correlated with clinical normal tissue reactions BACKGROUND Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms ( SNPs ) in c and i date genes . Few associations have been tested in independent validation studies . This prospect i ve study aim ed to vali date reported associations between genotype and radiation toxicity in a large independent data set . METHODS 92 ( of 98 attempted ) SNPs in 46 genes were successfully genotyped in 1613 patients : 976 received adjuvant breast radiotherapy in the Cambridge breast IMRT trial ( IS RCT N21474421 , n=942 ) or in a prospect i ve study of breast toxicity at the Christie Hospital , Manchester , UK ( n=34 ) . A further 637 received radical prostate radiotherapy in the MRC RT01 multicentre trial ( IS RCT N47772397 , n=224 ) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer ( CHHiP ) trial ( IS RCT N97182923 , n=413 ) . Late toxicity was assessed 2 years after radiotherapy with a vali date d photographic technique ( patients with breast cancer only ) , clinical assessment , and patient question naires . Association tests of genotype with overall radiation toxicity score and individual endpoints were undertaken in univariate and multivariable analyses . At a type I error rate adjusted for multiple testing , this study had 99 % power to detect a SNP , with minor allele frequency of 0·35 , associated with a per allele odds ratio of 2·2 . FINDINGS None of the previously reported associations were confirmed by this study , after adjustment for multiple comparisons . The p value distribution of the SNPs tested against overall toxicity score was not different from that expected by chance . INTERPRETATION We did not replicate previously reported late toxicity associations , suggesting that we can essentially exclude the hypothesis that published SNPs individually exert a clinical ly relevant effect . Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done 
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Conclusions The minor allele of rs13181 polymorphism may confer a protect effect against radiotoxicity .