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.