CSTF2 mediated mRNA N⁶-methyladenosine modification drives pancreatic ductal adenocarcinoma m⁶A 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.