Genomic landscapes reveal post-transcriptional modifier disruption in cholangiocarcinoma

Molecular variation of different geographic populations and cholangiocarcinoma (CCA) subtypes indicate CCA’s potential genomic heterogeneity and novel genomic features. We analyzed exome-sequencing data of 87 perihialr cholangiocarcinoma (pCCA) and 261 intrahepatic cholangiocarcinoma (iCCA) from 3 Asian centers (including 43 pCCAs and 24 iCCAs from our center). Patients with iCCA presented higher tumor mutation burden and copy number alteration burden (CNAB) than pCCA patients, and CNAB indicated a poorer pCCA prognosis. In our newly identified 12 significantly mutated genes and 5 focal CNA regions, post-transcriptional modification-related novel driver genes METTL14 and RBM10 are prone to occur in pCCA. We demonstrated the tumor-suppressing functional role of METTL14, a major RNA N6-adenosine methyltransferase (m6A), and its loss-of-function mutation R298H may function through m6A modification on new driver gene MACF1. Our results may be valuable for better understanding of post-transcriptional modification effects CCA development, and similarities and differences between pCCA and iCCA.