Risk SNP-mediated enhancer-promoter interaction drives colorectal cancer through both FADS2 and AP002754.2

Although genome-wide association studies (GWAS) have identified more than 100 colorectal cancer (CRC) risk loci, most of the biological mechanisms associated with these loci remain unclear. Here we first performed a comprehensive expression quantitative trait loci (eQTL) analysis in CRC tissues adjusted for multiple confounders to test the determinants of germline variants in established GWAS susceptibility loci on mRNA and long non-coding RNA (lncRNA) expression. Combining integrative functional genomic/epigenomic analyses and a large-scale population study consisting of 6,024 cases and 10,022 controls, we then prioritized rs174575 with a C>G change as a potential causal candidate for CRC at 11q12.2, as its G allele was associated with an increased risk of CRC (OR = 1.26, 95%CI = 1.17-1.36, P = 2.57×10-9). rs174575 acted as an allele-specific enhancer to distally facilitate expression of both FADS2 and lncRNA AP002754.2 via long-range enhancer-promoter interaction loops, which were mediated by E2F1. AP002754.2 further activated a transcriptional activator that upregulated FADS2 expression. FADS2, in turn, was overexpressed in CRC tumor tissues and functioned as a potential oncogene that facilitated CRC cell proliferation and xenograft growth in vitro and in vivo by increasing the metabolism of PGE2, an oncogenic molecule involved in CRC tumorigenesis. Our findings represent a novel mechanism by which a non-coding variant can facilitate long-range genome interactions to modulate the expression of multiple genes including not only mRNA, but also lncRNA, which provides new insights into the understanding of CRC etiology.