A rare missense variant in TCF7L2 associates with colorectal cancer risk by interacting with a GWAS-identified regulatory variant in the MYC enhancer

Jiang Chang, Jianbo Tian, Yang Yang, Rong Zhong, Jiaoyuan Li, Kan Zhai, Juntao Ke, Jiao Lou, Wei Chen, Beibei Zhu, Na Shen, Yi Zhang, Yajie Gong, Ying Zhu, Danyi Zou, Xiating Peng, Kun Huang, Xiaoping Miao

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified several common susceptible variants in gene regulatory regions. However, low-frequency or rare coding risk variants have not been systematically investigated in CRC patients from Chinese populations. In this study, we performed an exome-wide association analysis with 1,062 CRC patients 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 CRC risk: a novel rare missense variant in TCF7L2 (rs138649767, OR = 2.08, 95% CI: 1.69-2.57, P = 5.66×10-12) and a previous European GWAS-identified 3'-UTR variant in ATF1 (rs11169571, OR = 1.18, 95% CI: 1.13-1.24, P = 1.65×10-12). We found a significant interaction between the TCF7L2 missense variant rs138649767 and a previous GWAS-identified regulatory variant rs6983267 in the MYC enhancer (Pinteraction = 0.0002). Functional analysis of this variant revealed that TCF7L2 with rs138649767-A allele harbored the ability to activate the MYC enhancer with rs6983267-G allele and enhance CRC cell proliferation. Additionally, the ATF1 rs11169571 variant significantly correlated with ATF1 expression by affecting hsa-miR-1283 and hsa-miR-520d-5p binding. Further ChIP-seq and gene co-expression analyses showed that oncogenes NRAS and BRAF were activated by ATF1 in CRC. These results widen our understanding of the molecular basis of CRC risk and provide insight into pathways that might be targeted to prevent CRC.