Genetic polymorphisms in DNA repair genes and the risk of colorectal neoplasia

Background: Deficiencies in DNA repair are implicated in the etiology of colorectal neoplasia; however, few studies have investigated the relationship between common polymorphisms in DNA repair genes and the risk of colorectal neoplasia. Methods: To evaluate the association between common variants in DNA repair genes and advanced colorectal adenoma, a case-control study was conducted within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cases (n = 766) included participants diagnosed with advanced left-sided adenoma, and controls (n = 772) were subjects without evidence of a left-sided polyp by sigmoidoscopy. Nineteen single nucleotide polymorphisms were genotyped in four base excision repair genes ( APEX1, PARP1, POLB, and XRCC1). To examine the association between common polymorphisms in DNA repair genes and colorectal cancer, a case-cohort study was conducted within the CLUE II cohort. Twenty-two single nucleotide polymorphisms in eleven nucleotide excision repair genes ( ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, LIG1, RAD23B, RPA2, XPA, and XPC) and four polymorphisms in three mismatch repair genes (MSH3, MSH6, and MLH1) were genotyped in 250 colorectal cancer cases and 2,224 subcohort participants. Results: In the PLCO case-control study, the APEX1 51H and XRCC1 399Q variants were associated with a borderline significant decreased risk of colorectal adenoma. Among Caucasians, the homozygotes at two PARP1 loci (A284A and IVS13+118G>A) were associated with a decreased risk of colorectal adenoma, particularly histologically aggressive adenoma, suggesting that genetic variation in PARP1 may be important for adenomas more likely to progress to cancer. In the CLUE II case-cohort study, the nucleotide excision repair variants, ERCC6 1213G and XPC 492H, were associated with an increased risk of colorectal cancer. When the combined effects of these two polymorphisms were examined, the risk of colorectal cancer increased significantly with increasing number of variant alleles (Ptrend = 0.00003). Variants in the mismatch repair gene, MSH3, were associated with an increased risk of colorectal cancer, particularly proximal colon cancer, which is consistent with the hypothesis that defects in mismatch repair contribute to the etiology of proximal tumors. Conclusions: This dissertation suggests common polymorphisms in DNA repair genes may be associated with the risk of colorectal neoplasia.