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

Highlights

• 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.

Abstract

Background

Epigenetic 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.

Methods

A 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.

Results

The rs1800734 G-allele was associated with decreased risk of GC (GA or GG vs AA, OR = 0.72; 95% CI: 0.50–1.05; P_trend = 0.029). For combined effects, a dose–response manner was observed in which GC risk was increased with increasing number of at-risk genotypes (P_trend = 0.039); this manner mainly existed in MSI GC (P_trend = 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).

Conclusions

The 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.

Introduction

Gastric cancer (GC) is a major public health problem worldwide. Malfunction of DNA mismatch repair (MMR) is known to play important roles in the onset of GC (Velho et al., 2014). The core MMR genes include MSH2, MLH1, MSH3, MSH6, PMS1 and PMS2, other genes such as EXO1, TREX1, TP73 and MGMT also take part in MMR. The main function of the MMR system is to identify and repair incompatible DNA base pairings that are generated during DNA replication and recombination (Li, 2008). Defects in the MMR system can cause microsatellite instability (MSI), which presents as a somatic gain or loss in simple repeat (microsatellite) sequences of DNA. The accumulation of such errors increases the spontaneous mutation rate secondary to genome-wide instability and inactivates tumor suppressor genes, facilitating carcinogenesis. The incidence of MSI in GC has been reported from 15 to 30%, and MSI is associated with gastric carcinogenesis (Velho et al., 2014).

There are large interindividual differences in MMR capacity, owing largely to genetic and epigenetic alterations in the MMR genes among individual. Previously, epigenetic silencing of MLH1 by promoter hypermethylation was reported to be the main mechanism leading to MMR deficiency in GC, while which only partly explained the MSI phenotype of GC (Velho et al., 2014). In terms of somatic mutations in MMR genes, it was found to be rare in GC and did not explain its onset (Pinto et al., 2008). Less understood is the contribution of common polymorphisms in MMR genes to GC risk, though they have been associated with susceptibility and MSI phenotype to many cancers (Campbell et al., 2009, Nogueira et al., 2015, Lancaster et al., 2015, McCullough et al., 2014, Jung et al., 2006).

Recently, several studies have investigated the role of particular polymorphisms in MMR genes in gastric carcinogenesis; significant disease associations were identified with rs1047840 in EXO1 (Bau et al., 2009) and rs2303425, rs2303428 and rs3732183 in MSH2 (Xiao et al., 2012, Wang et al., 2012), indicating the necessity to further explore potential additional effects of other polymorphisms in MMR genes. However, no study has analyzed the relationship between relevant polymorphisms and MSI phenotype of GC, and therefore these associations remain inconclusive. Besides, gene–gene and gene–exposure interactions in MMR system are still unknown in GC. We sought to explore these issues with a case–control study.

Four polymorphisms in four MMR genes were selected in this study: rs1800734 in MLH1, rs2303428 in MSH2, rs735943 in EXO1, and rs11797 in TREX1. They were nonsynonymous polymorphisms or polymorphisms that were located at the 3′UTR or the splicing site, which were found to have a high genotype frequency among Chinese patients with GC in our preliminary study (unpublished results). Both rs1800734 and rs2303428 have been found to be associated with either cancer risk or clinical outcomes in many cancers, while their roles in gastric carcinogenesis are still controversial (Xu et al., 2012, He et al., 2013). The association between rs735943 or rs11797 and GC risk has never been studied, though a potential biologic function of these two polymorphisms had been suggested previously (Dong et al., 2009).