Identification of genetic variants in m 6 A modification genes associated with pancreatic cancer risk in the Chinese population

N 6-Methyladenosine (m 6 A) is the most prevalent modification of RNA in eukaryotes, and is associated with many cellular processes and even the development of cancers. We hypothesized that single-nucleotide polymorphisms (SNPs) in m 6 A modification genes, including its “writers”, “erasers” and “readers”, might affect the m 6 A functions and associate with the susceptibility to pancreatic ductal adenocarcinoma (PDAC). We first conducted a two-stage case–control study in Chinese population to interrogate all SNPs in 22 m 6 A modification genes. In the discovery stage, a total of 2735 SNPs were genotyped in 980 patients and 1991 controls. Then, the promising SNP was replicated in another independent population consisting of 858 cases and 2084 controls. As a result, we found the rs7495 in 3′UTR of hnRNPC was significantly associated with increased risk of PDAC in both stages (combined odds ratio = 1.22, 95% confidence interval = 1.12–1.32, P = 2.39 × 10 –6 ). To further reveal the biological function of rs7495 and hnRNPC, we performed a series of biochemical experiments. Luciferase reporter assays indicated that rs7495G allele promoted hnRNPC expression through disrupting a putative binding site for has-miR-183-3p. Cell viability assay demonstrated that knockdown of hnRNPC suppressed the proliferation of PDAC cells. RNA-seq analysis suggested that as an m 6 A “reader”, hnRNPC played an important role in RNA biological processes. In conclusion, our findings elucidated that rs7495G could confer higher risk of PDAC via promoting the expression of hnRNPC through a miRNA-mediated manner. These results provided a novel insight into the critical role of m 6 A modification in tumorigenesis.