Li Guangxiao, Hu Fulan, Yuan Fengshun, Fan Jialong, Yu Zhifu, Wu Zhiwei, Zhao Xiaojuan, Li Ye, Li Shuying, Rong Jiesheng, Cui Binbin, Dong Xinshu, Yuan Huiping, Zhao Yashuang
Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, Heilongjiang Province, People's Republic of China.
J Cancer Res Clin Oncol. 2015 Aug;141(8):1393-404. doi: 10.1007/s00432-014-1898-6. Epub 2015 Jan 6.
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.
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.
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).
Our findings suggested that intronic SNPs, gene-gene and gene-environment interactions in hMSH2 might be associated with susceptibility to CRC.
鉴于错配修复（MMR）系统在识别和去除DNA复制过程中发生的插入/缺失突变方面发挥着重要作用，与MMR系统受损相关的常见变异可能会增加结直肠癌（CRC）的风险。因此，我们旨在证明两个MMR基因（hMLH1和hMSH2）中的常见变异与CRC风险之间的关联。
我们对451例CRC患者和630例对照进行了hMLH1和hMSH2的10个内含子/启动子单核苷酸多态性（SNP）基因分型。使用优势比和95%置信区间估计基因型与CRC风险之间的关联。还研究了基因-基因相互作用以及基因-环境相互作用对CRC风险的影响。
我们发现hMSH2的IVS15-214T>C和IVS11 + 107A>G与CRC风险显著相关。在显性模型中，这两个SNP的变异携带者可分别将CRC风险降低31%（ORadj = 0.69，95% CI 0.53 - 0.91，p < 0.01）和33%（ORadj = 0.67，95% CI 0.47 - 0.95，p = 0.02）。此外，hMSH2的IVS7-212T>A、IVS11+183A>G和IVS8+719T>C与结肠癌而非直肠癌的易感性相关。ATTTGGGT和TCTTAGAC单倍型分别与CRC风险降低44%和45%相关，而ATTTGAGT和TTTCAGAC单倍型分别与CRC风险增加1.37倍和2.49倍相关。hMSH2的IVS11+107A>G、IVS11+183A>G和IVS8+719T>C之间存在显著的三向基因-基因相互作用（p < 0.01）。在hMSH2的IVS15-214T>C和IVS11+107A>G与谷物消费之间观察到显著的基因-环境相互作用（两者p < 0.01）。
我们的研究结果表明，hMSH2中的内含子SNP、基因-基因和基因-环境相互作用可能与CRC易感性相关。
