Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
Department of Medical Sciences, University of Turin, Turin, Italy.
Int J Cancer. 2020 Jan 15;146(2):363-372. doi: 10.1002/ijc.32516. Epub 2019 Jul 4.
Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.
个体间 DNA 修复系统的差异可能在调节结直肠癌个体发病风险中发挥作用。为了更好地确定 DNA 修复基因多态性对结肠癌和直肠癌风险的单独作用，我们使用来自结肠癌家族登记处 (CCFR) 和结直肠癌遗传与流行病学合作组 (GECCO) 的 GWAS 数据评估了 185 个 DNA 修复基因中的 15419 个单核苷酸多态性 (SNP)，该数据包括 8178 例结肠癌、2936 例直肠癌病例和 14659 例对照。rs1800734（MLH1 基因）与结肠癌风险相关（p 值=3.5×10-8），rs2189517（RAD51B 基因）与直肠癌风险相关（p 值=5.7×10-8）。结果接近 Bonferroni 校正的 p 值 5.8×10-8，具有统计学意义。经过二项式序列拟合优度（BSGoF）程序，有 94 个 SNP 与结直肠癌风险显著相关，并证实了错配修复（MMR）和同源重组途径分别与结肠癌和直肠癌相关。已知 MMR 基因缺陷对于家族性结直肠癌至关重要，但我们的研究结果表明，MLH1 中的特定遗传变异对于散发性结肠癌的个体易感性也很重要。与结肠癌风险相关的其他 SNP（例如，MGMT 中的 rs16906252）被发现影响结肠横截面上的 mRNA 表达水平，因此作为可能的顺式-eQTL 起作用，提示可能的致癌机制。
