The genomic landscape of cholangiocarcinoma reveals the disruption of post-transcriptional modifiers

Nat Commun. 2022 Jun 1;13(1):3061. doi: 10.1038/s41467-022-30708-7.


Molecular variation between geographical populations and subtypes indicate potential genomic heterogeneity and novel genomic features within CCA. Here, we analyze exome-sequencing data of 87 perihilar cholangiocarcinoma (pCCA) and 261 intrahepatic cholangiocarcinoma (iCCA) cases from 3 Asian centers (including 43 pCCAs and 24 iCCAs from our center). iCCA tumours demonstrate a higher tumor mutation burden and copy number alteration burden (CNAB) than pCCA tumours, and high CNAB indicates a poorer pCCA prognosis. We identify 12 significantly mutated genes and 5 focal CNA regions, and demonstrate common mutations in post-transcriptional modification-related potential driver genes METTL14 and RBM10 in pCCA tumours. Finally we demonstrate the tumour-suppressive role of METTL14, a major RNA N6-adenosine methyltransferase (m6A), and illustrate that its loss-of-function mutation R298H may act through m6A modification on potential driver gene MACF1. Our results may be valuable for better understanding of how post-transcriptional modification can affect CCA development, and highlight both similarities and differences between pCCA and iCCA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bile Duct Neoplasms* / genetics
  • Bile Duct Neoplasms* / pathology
  • Bile Ducts, Intrahepatic
  • Cholangiocarcinoma* / genetics
  • Cholangiocarcinoma* / pathology
  • Exome
  • Genomics
  • Humans
  • RNA-Binding Proteins / genetics


  • RBM10 protein, human
  • RNA-Binding Proteins