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. N6-methyladenosine (m6A) modification has important implications in different cancer subtypes. Here, the authors perform transcriptomic m6A profiling to identify two subtypes of pancreatic ductal adenocarcinoma with differential m6A modifications and different clinical outcomes, which is driven by m6A regulator CSTF2. [ABSTRACT FROM AUTHOR]