A Rare Missense Variant in TCF7L2 Associates with Colorectal Cancer Risk by Interacting with a GWAS-Identified Regulatory Variant in the MYC Enhancer

Abstract

Genome-wide association studies (GWAS) of colorectal cancer have identified several common susceptible variants in gene regulatory regions. However, low-frequency or rare coding risk variants have not been systematically investigated in patients with colorectal cancer from Chinese populations. In this study, we performed an exome-wide association analysis with 1,062 patients with colorectal cancer and 2,184 controls from a Chinese population. Promising associations were further replicated in two replication sets: replication stage I with 2,478 cases and 3,880 controls, and replication stage II with 3,761 cases and 4,058 controls. We identified two variants significantly associated with colorectal cancer risk: a novel rare missense variant in <i>TCF7L2</i> [rs138649767, OR = 2.08, 95% confidence interval (CI): 1.69-2.57, <i>P</i> = 5.66 × 10^-12] and a previous European GWAS-identified 3'-UTR variant in <i>ATF1</i> (rs11169571, OR = 1.18, 95% CI: 1.13-1.24, <i>P</i> = 1.65 × 10^-12). We found a significant interaction between the <i>TCF7L2</i> missense variant rs138649767 and a previous GWAS-identified regulatory variant rs6983267 in the <i>MYC</i> enhancer (<i>P</i>_interaction = 0.0002). Functional analysis of this variant revealed that TCF7L2 with rs138649767-A allele harbored the ability to activate the <i>MYC</i> enhancer with rs6983267-G allele and enhance colorectal cancer cell proliferation. In addition, the <i>ATF1</i> rs11169571 variant significantly correlated with <i>ATF1</i> expression by affecting hsa-miR-1283 and hsa-miR-520d-5p binding. Further ChIP-seq and gene coexpression analyses showed that oncogenes <i>NRAS</i> and <i>BRAF</i> were activated by ATF1 in colorectal cancer. These results widen our understanding of the molecular basis of colorectal cancer risk and provide insight into pathways that might be targeted to prevent colorectal cancer.<b>Significance:</b> Exome-wide association analysis identifies a rare missense variant in <i>TCF7L2</i> and a common regulatory variant in <i>ATF1</i> as susceptibility factors of colorectal cancer.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/78/17/5164/F1.large.jpg <i>Cancer Res; 78(17); 5164-72. ©2018 AACR</i>.