Polymorphisms in mismatch repair genes are associated with risk and microsatellite instability of gastric cancer, and interact with life exposures

• The MLH1 rs1800734 polymorphism is associated with risk of gastric cancer.
• At-risk genotypes of mismatch repair genes jointly contribute to risk of gastric cancer.
• At-risk genotypes jointly contribute to microsatellite instability of gastric cancer.
• Life exposures modify risk of gastric cancer, stratified by mismatch repair genotypes.

BackgroundEpigenetic alterations of DNA mismatch repair (MMR) genes are associated with risk of gastric cancer (GC) by causing microsatellite instability (MSI). Less understood is the association of common polymorphisms in MMR genes with the risk and MSI phenotype of GC.MethodsA hospital-based study was conducted in China with 423 cases and 454 matched controls. Four potentially functional polymorphisms were selected and analyzed: rs1800734 in MLH1, rs2303428 in MSH2, rs735943 in EXO1, and rs11797 in TREX1.ResultsThe rs1800734 G-allele was associated with decreased risk of GC (GA or GG vs AA, OR = 0.72; 95% CI: 0.50–1.05; Ptrend = 0.029). For combined effects, a dose–response manner was observed in which GC risk was increased with increasing number of at-risk genotypes (Ptrend = 0.039); this manner mainly existed in MSI GC (Ptrend = 0.047) rather than in microsatellite stability GC, though neither single polymorphism was linked with MSI. For exposures, modified effects were observed from green tea drinking and soy foods intake on rs11797 (P for interaction = 0.007 and 0.016, respectively).ConclusionsThe MLH1 rs1800734 polymorphism is associated with GC risk. Those at-risk genotypes have a joint effect on GC risk, which contributes to the MSI phenotype of GC. Life exposures modify GC risk, stratified by MMR genotypes.