Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity

Nat Commun. 2015 Jan 30;6:6120. doi: 10.1038/ncomms7120.


Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying biliary phenotype (LCB). LCB is second in the incidence for liver cancers with and without chronic hepatitis background and more aggressive than hepatocellular carcinoma (HCC). To gain insight into its molecular alterations, we performed whole-genome sequencing analysis on 30 LCBs. Here we show, the genome-wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs, whereas those of hepatitis-negative LCBs diverged. The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators (BAP1, PBRM1 and ARID2), a synapse organization gene (PCLO), IDH genes and KRAS. The frequencies of KRAS and IDHs mutations, which are associated with poor disease-free survival, were significantly higher in hepatitis-negative LCBs. This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Bile Duct Neoplasms / genetics
  • Bile Ducts, Intrahepatic
  • Carcinoma, Hepatocellular / genetics
  • Cholangiocarcinoma / genetics
  • Cytoskeletal Proteins / genetics
  • DNA-Binding Proteins
  • Female
  • Hepatitis / genetics
  • Hepatitis / physiopathology
  • Humans
  • Liver Neoplasms / genetics*
  • Male
  • Middle Aged
  • Mutation / genetics
  • Neuropeptides / genetics
  • Nuclear Proteins / genetics
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Telomerase / genetics
  • Transcription Factors / genetics
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics
  • ras Proteins / genetics


  • ARID2 protein, human
  • BAP1 protein, human
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • KRAS protein, human
  • Neuropeptides
  • Nuclear Proteins
  • PBRM1 protein, human
  • PCLO protein, human
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • TERT protein, human
  • Telomerase
  • Ubiquitin Thiolesterase
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins