title: DNA mismatch repair network gene polymorphism as a susceptibility factor for pancreatic cancer.
abstract: 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.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Dong
authors.forename: Yanan
authors.initials: Y
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Chang
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Donghui
authors.initials: D
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D053843:DNA Mismatch Repair / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D019853:O(6)-Methylguanine-DNA Methyltransferase