Common genetic variation in ETV6 is associated with colorectal cancer susceptibility

Abstract

Genome-wide association studies (GWASs) 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 tumours than in paired normal tissues. Our findings highlight the potential importance of genetic variation in ETV6 conferring susceptibility to colorectal cancer.

Risk of eighteen genome-wide association study-identified genetic variants for colorectal cancer and colorectal adenoma in Han Chinese

“…Recently, a GWAS of colorectal cancer in East Asians [65] and two in Chinese (labeled as Chinese 1 [66] and Chinese 2 [67]) identified new novel loci for colorectal cancer risk. Most of our variants were included in the three GWAS (Supplementary Table S2).…”

ETV6 in hematopoiesis and leukemia predisposition

“…The tumors included Stage III colorectal adenocarcinoma at age 45(17), stage IV colon cancer at age 43(17), breast fibroadenoma (age 35) and meningioma (age 43) in same patient (18) (22), breast carcinoma at age 49 (18) (22), breast fibroadenoma at age 14(22), duodenal adenocarcinoma (19)and renal cell carcinoma (19) (ages not reported). Although somatic variants in ETV6 have been described in solid tumors such as GI cancers (25), given the small number of cases reported in familial ETV6 studies, further investigation is needed to understand the role of ETV6 in promoting the development of solid tumor malignancies.…”

Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions

“…Indeed, in a cohort of over 4,000 apparently sporadic B-ALL cases, approximately 1% were found to harbor germline ETV6 variants thought to contribute to leukemogenesis (52). Less often, solid tumors have been observed, and a recent report suggests that a germline ETV6 variant is associated with increased risk of colorectal cancer as adults (54). Therefore, it is possible that germline ETV6 mutations lead to a more general cancer predisposition, with B-ALL as the greatest risk.…”