Selected polymorphisms of DNA repair genes and risk of pancreatic cancer

Background: Genetic variants of DNA repair genes may contribute to pancreatic carcinogenesis. O-6-methylguanine-DNA methyltransferase (MGMT) is the major protein that removes alkylating DNA adducts, and apurinic/apyrimidinic endonuclease 1 (APEI) 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 (Leu(84)Phe and Ile(143)Val), APE1 (Asp(148)Glu), and XRCC1 (Arg(194)Trp and Arg(399)Gln) 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 XRCC1(194) polymorphism had a significant interaction with the APE1(141) (p = 0.005) or MGMT(84) 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. (c) 2006 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved.