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

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

Author information

1
1] European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy [2].
2
1] European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy [2] Division of Cancer Studies, King's College London, London SE1 1UL, UK [3].
3
VIB Center for the Biology of Disease, KU Leuven Center for Human Genetics, O&N4 Herestraat 49 box 602, B-3000 Leuven, Belgium.
4
European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
5
Paediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Piazza OMS - Organizzazione Mondiale della Sanità 1, 24128 Bergamo, Italy.
6
Department of Pathology, Ospedale Papa Giovanni XXIII, Piazza OMS - Organizzazione Mondiale della Sanità 1, 24128 Bergamo, Italy.
7
Institut National de la Santé et de la Recherche Médicale (INSERM) U785, University Paris-Sud, France, Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif F94800, France.
8
University Hospital for Children and Adolescents, University of Tuebingen, 72076 Tuebingen, Germany.
9
Institute of Liver Studies, King's College London, London SE5 9RS, UK.
10
Institute of Liver Studies, King's College Hospital, London SE5 9RS, UK.
11
1] European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy [2] Division of Cancer Studies, King's College London, London SE1 1UL, UK.

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.

PMID:
24819516
DOI:
10.1038/ncomms4850
[Indexed for MEDLINE]

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