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. 2015 Aug;141(8):1393-404.
doi: 10.1007/s00432-014-1898-6. Epub 2015 Jan 6.

Intronic and promoter polymorphisms of hMLH1/hMSH2 and colorectal cancer risk in Heilongjiang Province of China

Guangxiao Li  1 , Fulan Hu, Fengshun Yuan, Jialong Fan, Zhifu Yu, Zhiwei Wu, Xiaojuan Zhao, Ye Li, Shuying Li, Jiesheng Rong, Binbin Cui, Xinshu Dong, Huiping Yuan, Yashuang Zhao
Affiliations

Intronic and promoter polymorphisms of hMLH1/hMSH2 and colorectal cancer risk in Heilongjiang Province of China

Guangxiao Li et al. J Cancer Res Clin Oncol. 2015 Aug.

Abstract

Purpose: Given that mismatch repair (MMR) system plays an important role in recognizing and removing insertion/deletion mutations which occur during DNA replication, common variants associated with impaired MMR system may thus increase risk of colorectal cancer (CRC). Therefore, we aimed to demonstrate the associations between common variants in two MMR genes (hMLH1 and hMSH2) and CRC risk.

Methods: We genotyped 10 intronic/promoter single-nucleotide polymorphisms (SNPs) of hMLH1 and hMSH2 in 451 CRC patients and 630 controls. Associations between genotypes and CRC risk were estimated using odds ratios and 95 % confidence intervals. Gene-gene interactions, as well as gene-environment interactions on CRC risk were also investigated.

Results: We found that IVS15-214T>C and IVS11 + 107A>G of hMSH2 were significantly associated with CRC risk. In dominant model, variant carriers of the two SNPs could decrease risk of CRC by 31 % (ORadj = 0.69, 95 % CI 0.53-0.91, p < 0.01) and 33 % (ORadj = 0.67, 95 % CI 0.47-0.95, p = 0.02), respectively. In addition, IVS7-212T>A, IVS11+183A>G and IVS8+719T>C of hMSH2 were associated with the susceptibility to colon cancer rather than rectal cancer. ATTTGGGT and TCTTAGAC haplotypes were associated with 44 and 45 % decreased risk of CRC, respectively, while ATTTGAGT and TTTCAGAC haplotypes were associated with 1.37-fold and 2.49-fold increased risk of CRC, respectively. There was a significant three-way gene-gene interaction among hMSH2 IVS11+107A>G, IVS11+183A>G and IVS8+719T>C (p < 0.01). Significant gene-environment interactions were observed between hMSH2 IVS15-214T>C and IVS11+107A>G and cereals consumption (both with p < 0.01).

Conclusions: Our findings suggested that intronic SNPs, gene-gene and gene-environment interactions in hMSH2 might be associated with susceptibility to CRC.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Best three-way gene–gene interaction model that calculated by MDR: high-risk genotype combinations are in gray and low-risk genotype combinations in white; the left bar represents the colorectal cancer group, and the right bar represents the controls
See this image and copyright information in PMC

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