Research paperPolymorphisms in mismatch repair genes are associated with risk and microsatellite instability of gastric cancer, and interact with life exposures
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).
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Subjects
The cases studied at the Affiliated Hospital of Jiangsu University were unrelated Han Chinese newly diagnosed with GC in the period from September 2008 to March 2012. A board-certified gastro-pathologist reviewed each GC diagnosis. The selection of controls and interview of subjects have been previously described in detail (Wang et al., 2012). For each case, up to 2 healthy controls were selected.
Initially, 446 GC patients and 895 controls agreed to participate in the study. Among the GC
Characteristics of the studied subjects
There were no significant differences between the cases and controls for mean age or gender distribution, suggesting that the matching based on these two variables was adequate. Hp infection, smoking, alcohol drinking, and high intake of pickled vegetables were found to be risk factors, while green tea drinking, high intake of milk/dairy products, and high fruit consumption were found to be protective factors for GC (Table 1).
Associations between MMR genotypes and GC risk
All genotype distributions among the controls were in Hardy–Weinberg
Discussion
In this case–control study, we investigated the association of four polymorphisms in four MMR genes with GC risk in a Chinese population. To our knowledge, this is the first report about the statistically significant association between rs1800734 and GC risk. Further, at-risk genotypes were found to jointly contribute to GC risk, and this combined effect mainly existed in MSI GC rather than in MSS GC, which provides the first evidence of the effect of MMR polymorphisms on MSI phenotype of GC.
Competing interests
No competing interests were disclosed.
The following are the supplementary data related to this article.
Acknowledgments
We thank the patients and controls who participated in this study. This project was supported by grants from the National Natural Science Foundation of China (grant number: 81301765) and the Natural Science Foundation of Jiangsu Province (grant number: BK20141490).
References (36)
- et al.
Variations in exon 7 of the MSH2 gene and susceptibility to gastrointestinal cancer in a Chinese population
Cancer Genet. Cytogenet.
(2006) - et al.
Human exonuclease I is required for 5′ and 3′ mismatch repair
J. Biol. Chem.
(2002) - et al.
The hMLH1 promoter polymorphisms and cancer susceptibility in Asian populations: a meta-analysis
Gene
(2013) - et al.
Translational control by the 3′-UTR: the ends specify the means
Trends Biochem. Sci.
(2003) - et al.
Somatic mutations in mismatch repair genes in sporadic gastric carcinomas are not a cause but a consequence of the mutator phenotype
Cancer Genet. Cytogenet.
(2008) - et al.
In vivo non-enzymatic repair of DNA oxidative damage by polyphenols
Cell Biol. Int.
(2009) - et al.
Polymorphisms in MSH2 gene and risk of gastric cancer, and interactions with lifestyle factors in a Chinese population
Cancer Epidemiol.
(2012) - et al.
Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease
Cell
(2007) - et al.
Single-nucleotide polymorphism of the Exo1 gene: association with gastric cancer susceptibility and interaction with smoking in Taiwan
Chin. J. Phys.
(2009) - et al.
Oxidative stress and the DNA mismatch repair pathway
Antioxid. Redox Signal.
(2013)
Quasimonomorphic mononucleotide repeats for high-level microsatellite instability analysis
Dis. Markers
Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors
Gut
Evidence for heritable predisposition to epigenetic silencing of MLH1
Int. J. Cancer
Dietary polyphenols protect against N-nitrosamines and benzo(a)pyrene-induced DNA damage (strand breaks and oxidized purines/pyrimidines) in HepG2 human hepatoma cells
Eur. J. Nutr.
Significant associations of mismatch repair gene polymorphisms with clinical outcome of pancreatic cancer
J. Clin. Oncol.
Isoflavones in aglycone solution enhance ultraviolet B-induced DNA damage repair efficiency
Clin. Exp. Dermatol.
Polymorphisms in the hMSH2 gene and the risk of primary lung cancer
Cancer Epidemiol. Biomark. Prev.
Genome-wide DNA methylation modified by soy phytoestrogens: role for epigenetic therapeutics in prostate cancer?
OMICS
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Xiaoqin Li and Haifeng Zhu equally contributed to this manuscript.