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DNA mismatch repair network gene polymorphism as a susceptibility factor for pancreatic cancer

DNA repair plays a critical role in human cancers. We hypothesized that DNA mismatch repair gene variants are associated with risk of pancreatic cancer. We retrospectively genotyped 102 single‐nucleotide polymorphisms (SNPs) of 13 mismatch repair related genes in 706 patients with pancreatic cancer and 706 cancer‐free controls using the mass spectroscopy‐based MassArray method. Association of genotype with pancreatic cancer risk was tested by multivariate logistic regression models. A significance level of P ≤ 0.0015 was set at the false discovery rate (FDR) <1% using the Beta‐Uniform Mixture method. We found 28 SNPs related to altered pancreatic cancer risk (P < 0.05). Adjusting for multiple comparisons, MGMT I143V AG/GG, PMS2 IVS1‐1121C > T TC/TT, and PMS2L3 Ex1 + 118C > T CT/TT genotypes showed significant main effects on pancreatic cancer risk at FDR <1% with OR (95% CI) of 0.60 (0.46–0.80), 1.44 (1.14–1.81), and 5.54 (2.10–14.61), respectively (P ≤ 0.0015). To demonstrate genotype–phenotype association, we measured O 6‐ethylguanosine (O 6‐EtGua) adduct levels in vitro by immunoslot blot assay in lymphocytes treated with N‐ethyl‐N‐nitrosourea (ENU) in 297 case/control subjects. MGMT I143V GG, MGMT K178R GG, MSH6 G39E AG/AA, PMS2L3 IVS3 + 9A > G GA and TP73 IVS1‐7449G > C CG/CC genotypes correlated with a higher level of ENU‐induced DNA adducts. Haplotypes of MGMT, MSH6, PMS2, PMS2L3, and TP73 were significantly associated with pancreatic cancer risk (P ≤ 0.0015). Our findings suggest that mismatch repair gene variants may affect susceptibility to pancreatic cancer. © 2011 Wiley Periodicals, Inc.