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

Fabio Iannelli, Agnese Collino, Shruti Sinha, Enrico Radaelli, Paola Nicoli, Lorenzo D'Antiga, Aurelio Sonzogni, Jamila Faivre, Marie Annick Buendia, Ekkehard Sturm, Richard J. Thompson, A. S. Knisely, Gioacchino Natoli, Serena Ghisletti, Francesca D. Ciccarelli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number3850
JournalNature Communications
Volume5
DOIs
Publication statusPublished - May 13 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)
  • Medicine(all)

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