Abstract
BackgroundWe analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study.Methods/Principal FindingsThe analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)per allele = 0.66; 95% credible interval (CI) = 0.44–1.00) and rs6005835 (median ORper allele = 0.69; 95% CI = 0.53–0.91) in CHEK2, rs2078486 (median ORper allele = 1.65; 95% CI = 1.21–2.25) and rs12951053 (median ORper allele = 1.65; 95% CI = 1.20–2.26) in TP53, rs411697 (median OR rare homozygote = 0.53; 95% CI = 0.35 – 0.79) in BACH1 and rs10131 (median OR rare homozygote = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study.Conclusions/SignificanceBased on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.
Highlights
Ovarian cancer is the leading cause of mortality among gynecologic cancers [1]
North Carolina Ovarian Cancer Study (NCOCS) Candidate DNA Repair Gene Analysis In the marginal single nucleotide polymorphism (SNP)-at-a-time analysis of the 484 nonredundant SNPs passing quality control, S = 77 SNPs passed the marginal screen. (The results of the screening phase of analysis, including median odd ratios (ORs), 95% credible intervals (CIs) and minor allele frequency (MAF) for all 484 SNPs are shown in Table S2.) We ran Multi-level Inference for SNP Association (MISA) using the 77 SNPs that passed the screen with parameters a = 1/8 and S = 77, which leads to marginal prior odds of association in this subset of 1/axS = 0.0016
The SNP-specific Bayes Factors are composite measures that average over statistical models of association that include that SNP while adjusting for other potentially associated SNPs and their genetic parameterizations
Summary
The highly lethal serous histological type comprises about two-thirds of cases and causes most diseaserelated deaths Reproductive factors such as high parity, oral contraceptive use, breast feeding, hysterectomy, and tubal ligation protect against ovarian cancer [2], whereas infertility and endometriosis increase risk [3,4]. The biological mechanisms that underlie these risk factors are not well understood, but inflammation-related oxidative stress has been proposed as a unifying theory by which these risk factors could cause genomic damage leading to the development of cancer [5,6,7,8,9] If this theory is correct, it is plausible that the risk of ovarian cancer would be modified by common genetic variants that affect the efficacy of DNA repair genes [10,11]. We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a populationbased, case-control study
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