Selected polymorphisms of DNA repair genes and risk of pancreatic cancer

Background: Genetic variants of DNA repair genes may contribute to pancreatic carcinogenesis. O6-methylguanine-DNA methyltransferase (MGMT) is the major protein that removes alkylating DNA adducts, and apurinic/apyrimidinic endonuclease 1 (APE1) and X-ray repair cross-complementing group 1 (XRCC1) play important roles in the base excision repair pathway. Methods: We investigated the association between polymorphisms of MGMT (Leu84Phe and Ile143Val), APE1 (Asp148Glu), and XRCC1 (Arg194Trp and Arg399Gln) and risk of pancreatic cancer in a case-control study. Exposure information from 384 patients with primary pancreatic ductal adenocarcinoma and 357 cancer-free healthy controls were collected and genomic DNAs were genotyped for five markers. Controls were frequency matched to patients by age at enrollment (±5 years), gender, and race. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by using unconditional logistic regression models. Results: There was no significant main effect or interaction with smoking of these genetic variants on the risk of pancreatic cancer. However, the XRCC1194 polymorphism had a significant interaction with the APE1148 (p = 0.005) or MGMT84 polymorphism (p = 0.02) in modifying the risk of pancreatic cancer. Conclusions: This study suggests that polymorphisms of genes involved in the repair of alkylating DNA adduct and DNA base damage may play a role in modulating the risk of pancreatic cancer. Larger studies are required to validate these preliminary findings. The mechanism of the combined genotype effects remains to be elucidated.