CSTF2 mediated mRNA N 6 -methyladenosine modification drives pancreatic ductal adenocarcinoma m 6 A subtypes.

N 6 -methyladenosine (m 6 A) modification of gene transcripts plays critical roles in cancer. Here we report transcriptomic m 6 A profiling in 98 tissue samples from 65 individuals with pancreatic ductal adenocarcinoma (PDAC). We identify 17,996 m 6 A peaks with 195 hyper-methylated and 93 hypo-methylated in PDAC compared with adjacent normal tissues. The differential m 6 A modifications distinguish two PDAC subtypes with different prognosis outcomes. The formation of the two subtypes is driven by a newly identified m 6 A regulator CSTF2 that co-transcriptionally regulates m 6 A installation through slowing the RNA Pol II elongation rate during gene transcription. We find that most of the CSTF2-regulated m 6 As have positive effects on the RNA level of host genes, and CSTF2-regulated m 6 As are mainly recognized by IGF2BP2, an m 6 A reader that stabilizes mRNAs. These results provide a promising PDAC subtyping strategy and potential therapeutic targets for precision medicine of PDAC.