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

N⁶-methyladenosine (m⁶A) modification of gene transcripts plays critical roles in cancer. Here we report transcriptomic m⁶A profiling in 98 tissue samples from 65 individuals with pancreatic ductal adenocarcinoma (PDAC). We identify 17,996 m⁶A peaks with 195 hyper-methylated and 93 hypo-methylated in PDAC compared with adjacent normal tissues. The differential m⁶A modifications distinguish two PDAC subtypes with different prognosis outcomes. The formation of the two subtypes is driven by a newly identified m⁶A regulator CSTF2 that co-transcriptionally regulates m⁶A installation through slowing the RNA Pol II elongation rate during gene transcription. We find that most of the CSTF2-regulated m⁶As have positive effects on the RNA level of host genes, and CSTF2-regulated m⁶As are mainly recognized by IGF2BP2, an m⁶A reader that stabilizes mRNAs. These results provide a promising PDAC subtyping strategy and potential therapeutic targets for precision medicine of PDAC.