Common genetic variation in ETV6 is associated with colorectal cancer susceptibility

Genome-wide association studies (GWAS) have identified multiple susceptibility loci for colorectal cancer, but much of heritability remains unexplained. To identify additional susceptibility loci for colorectal cancer, here we perform a GWAS in 1,023 cases and 1,306 controls and replicate the findings in seven independent samples from China, comprising 5,317 cases and 6,887 controls. We find a variant at 12p13.2 associated with colorectal cancer risk (rs2238126 in ETV6, P = 2.67 × 10-10). We replicate this association in an additional 1,046 cases and 1,076 controls of European ancestry (P = 0.034). The G allele of rs2238126 confers earlier age at onset of colorectal cancer (P = 1.98 × 10-6) and reduces the binding affinity of transcriptional enhancer MAX. The mRNA level of ETV6 is significantly lower in colorectal tumors than in paired normal tissues. Our findings highlight the potential importance of genetic variation in ETV6 conferring susceptibility to colorectal cancer.全基因组关联研究（Genome-wide association studies, GWAS）已识别出多个结直肠癌的易感位点，但仍有大量遗传度尚未得到阐明。为识别结直肠癌的额外易感位点，本研究对1023名结直肠癌患者与1306名对照人群开展全基因组关联研究，并在7个独立的中国人群队列中对研究结果进行验证，该验证队列共纳入5317名患者与6887名对照。本研究在12p13.2区域发现一个与结直肠癌风险相关的变异（ETV6基因内的rs2238126，P=2.67×10⁻¹⁰）。我们在另外1046名欧洲血统的结直肠癌患者与1076名对照中验证了该关联（P=0.034）。rs2238126的G等位基因与结直肠癌更早的发病年龄相关（P=1.98×10⁻⁶），同时会降低转录增强子MAX的结合亲和力。结直肠癌肿瘤组织中ETV6的mRNA水平显著低于配对的正常组织。本研究结果凸显了ETV6基因的遗传变异在结直肠癌易感性中的潜在重要作用。