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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.

SUBMITTER: Dong X

PROVIDER: S-EPMC3179809 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Dong Xiaoqun X Li Yanan Y Chang Ping P Hess Kenneth R KR Abbruzzese James L JL Li Donghui D

Molecular carcinogenesis 20110616 6

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 significan ...[more]

PMID: 21681824

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Project description:Thyroid cancer (TC) is the most common endocrine malignancy and its incidence continues to rise worldwide. Ionizing radiation exposure is the best established etiological factor. Heritability is high; however, despite valuable contribution from recent genome-wide association studies, the current understanding of genetic susceptibility to TC remains limited. Several studies suggest that altered function or expression of the DNA mismatch repair (MMR) system may contribute to TC pathogenesis. Therefore, the present study aimed to evaluate the potential role of a panel of MMR single nucleotide polymorphisms (SNPs) on the individual susceptibility to well-differentiated TC (DTC). A case-control study was performed involving 106 DTC patients and 212 age- and gender-matched controls, who were all Caucasian Portuguese. Six SNPs present in distinct MMR genes (MLH1 rs1799977, MSH3 rs26279, MSH4 rs5745325, PMS1 rs5742933, MLH3 rs175080 and MSH6 rs1042821) were genotyped through TaqMan® assays and genotype-associated risk estimates were calculated. An increased risk was observed in MSH6 rs1042821 variant homozygotes [adjusted odds ratio (OR)=3.42, 95% CI: 1.04-11.24, P=0.04, under the co-dominant model; adjusted OR=3.84, 95% CI: 1.18-12.44, P=0.03, under the recessive model]. The association was especially evident for the follicular histotype and female sex. The association was also apparent when MSH6 was analysed in combination with other MMR SNPs such as MSH3 rs26279. Interestingly, two other SNP combinations, both containing the MSH6 heterozygous genotype, were associated with a risk reduction, suggesting a protective effect for these genotype combinations. These data support the idea that MMR SNPs such as MSH6 rs1042821, alone or in combination, may contribute to DTC susceptibility. This is coherent with the limited evidence available. Nevertheless, further studies are needed to validate these findings and to establish the usefulness of these SNPs as genetic susceptibility biomarkers for DTC so that, in the near future, cancer prevention policies may be optimized under a personalized medicine perspective.

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

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

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