A germline variant in the BET1L 3'-UTR confers colorectal cancer susceptibility by reducing miRNA binding and m6A modification.

Genetic variants in regions encoding 3'-untranslated regions (UTR) of mRNA potentially alter miRNA binding affinity and N6-methyladenosine (m6A) levels to affect gene expression. A better understanding of the association of these variants with colorectal cancer susceptibility could facilitate development of cancer prevention and treatment approaches. Here, we analyzed miRNA expression profiles and integrated genetic analyses from 8,533 individuals to evaluate the effects of altered miRNA-binding sites on colorectal cancer risk. The single nucleotide polymorphism rs11245997 in the BET1L 3'-UTR was significantly associated with colorectal cancer risk. The rs11245997 A allele facilitated BET1L expression by disrupting miR-140-3p binding. It also reduced BET1L m6A modification, which upregulated BET1L mRNA and protein expression levels through a mechanism mediated by the m6A methyltransferases (METTL14 and WTAP) and the m6A demethylase ALKBH5. Moreover, higher expression of BET1L was associated with advanced tumor stages and poor patient prognosis. Increased BET1L expression promoted growth of colorectal cancer cells in vitro and in vivo, which could be partially rescued with miR-140-3p overexpression. RNA-Seq and pathway analyses indicated that BET1L is associated with the steroid biosynthesis pathway through regulation of HSD17B7, CYP27B1 and COMT. These findings provide insights into the involvement of genetic variants of BET1L in the development and progression of colorectal cancer.