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

  • Original Article – Cancer Research
  • Published:
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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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Acknowledgments

This work was funded by Natural Sciences Foundation of China (NSFC) and the Grant numbers were 30671801 and 30371243.

Conflict of interest

The authors declare no competing financial interests.

Ethical standard

Our study has been approved by the Institutional Research Board of Harbin Medical University and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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Authors and Affiliations

  1. Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, Heilongjiang Province, People’s Republic of China

    Guangxiao Li, Fulan Hu, Fengshun Yuan, Jialong Fan, Zhifu Yu, Zhiwei Wu, Xiaojuan Zhao, Ye Li, Shuying Li & Yashuang Zhao

  2. Department of Orthopedics Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China

    Jiesheng Rong

  3. Department of Colorectal Surgery, Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China

    Binbin Cui

  4. Center of Tumor Therapy, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China

    Xinshu Dong

  5. Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China

    Huiping Yuan

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  1. Guangxiao Li
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  2. Fulan Hu
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  3. Fengshun Yuan
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  5. Zhifu Yu
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  6. Zhiwei Wu
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  7. Xiaojuan Zhao
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  8. Ye Li
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  9. Shuying Li
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  10. Jiesheng Rong
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  11. Binbin Cui
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  12. Xinshu Dong
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  13. Huiping Yuan
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  14. Yashuang Zhao
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Corresponding author

Correspondence to Yashuang Zhao.

Additional information

Guangxiao Li and Fulan Hu have contributed equally to this work.

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Li, G., Hu, F., Yuan, F. et al. Intronic and promoter polymorphisms of hMLH1/hMSH2 and colorectal cancer risk in Heilongjiang Province of China. J Cancer Res Clin Oncol 141, 1393–1404 (2015). https://doi.org/10.1007/s00432-014-1898-6

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