Genetic variants of DNA repair genes may contribute to their altered capacity to repair endogenous and exogenous DNA damage. Although rare mutations in mismatch repair genes are known to lead to hereditary non-polyposis colorectal cancer, to date studies investigating common single nucleotide polymorphisms (SNPs) in DNA repair genes and colorectal cancer or adenoma risk have only examined a small number of variants in a limited number of genes. We conducted a comprehensive analysis of DNA repair gene polymorphisms and colorectal adenoma risk using a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Effect modification by smoking, which is a known risk factor for adenoma, was also explored. A total of 1,338 advanced, left-sided colorectal adenoma cases and 1,503 frequency-matched controls without evidence of a left-sided polyp on sigmoidoscopy were included in the current study. Using DNA extracted from blood specimens, 3,401 tag SNPs in 153 DNA repair genes were genotyped. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations between genetic variants and adenoma risk assuming a log-additive model for the genotype. Among Caucasians, 30 SNPs were associated with adenoma risk at p<0.01. The most significant finding was for a non-synonymous SNP in EXO1 (rs9350), which was predicted to be deleterious using the SIFT and PolyPhen databases. The C allele at EXO1 rs9350 was associated with a 1.30-fold increased risk (95% CI=1.11-1.51, P=0.001). The association appeared to be limited to smokers (OR=1.54, 95% CI=1.26-1.89) with the strongest risk for current smokers (OR=2.15, 95% CI=1.27-3.65), and an intermediate risk for former smokers (OR=1.45, 95% CI=1.14-1.82), compared to never smokers (OR=0.98, 95% CI=0.76-1.25) that exhibited no increased risk (Pinteraction=0.002). Among the top findings, a SNP (rs17503908) in ATM with an overall OR of 0.75 (95% CI=0.63-0.91) was also modified by smoking (Pinteraction=0.006); the T allele at ATM rs17503908 was protective among never smokers (OR=0.55, 95% CI=0.40-0.76) but not among smokers (OR=0.89, 95% CI=0.70-1.13). The study suggests that polymorphisms in EXO1 and ATM may be associated with risk of advanced colorectal adenoma with the effects modified by tobacco smoking status. Our findings warrant extended investigations of these associations for colorectal cancer risk.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1867.