Massive gene amplification drives paediatric hepatocellular carcinoma caused by bile salt export pump deficiency

Nat Commun. 2014 May 13;5:3850. doi: 10.1038/ncomms4850.

Abstract

Hepatocellular carcinoma (HCC) is almost invariably associated with an underlying inflammatory state, whose direct contribution to the acquisition of critical genomic changes is unclear. Here we map acquired genomic alterations in human and mouse HCCs induced by defects in hepatocyte biliary transporters, which expose hepatocytes to bile salts and cause chronic inflammation that develops into cancer. In both human and mouse cancer genomes, we find few somatic point mutations with no impairment of cancer genes, but massive gene amplification and rearrangements. This genomic landscape differs from that of virus- and alcohol-associated liver cancer. Copy-number gains preferentially occur at late stages of cancer development and frequently target the MAPK signalling pathway, and in particular direct regulators of JNK. The pharmacological inhibition of JNK retards cancer progression in the mouse. Our study demonstrates that intrahepatic cholestasis leading to hepatocyte exposure to bile acids and inflammation promotes cancer through genomic modifications that can be distinguished from those determined by other aetiological factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters / deficiency
  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Carcinoma, Hepatocellular / genetics*
  • Child
  • Child, Preschool
  • Cholestasis, Intrahepatic / genetics*
  • DNA Copy Number Variations / genetics*
  • Female
  • Gene Amplification*
  • Hepatocytes / metabolism*
  • Humans
  • Infant
  • Liver Neoplasms / genetics*
  • Liver Neoplasms, Experimental / genetics*
  • MAP Kinase Signaling System / genetics*
  • Male
  • Mice
  • Mice, Knockout

Substances

  • ABCB11 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters
  • P-glycoprotein 2

Supplementary concepts

  • Cholestasis, progressive familial intrahepatic 2

Associated data

  • SRA/SRP040691
  • SRA/SRP040712
  • SRA/SRP040716