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 () and Francesca D. Ciccarelli ()
Additional contact information
Fabio Iannelli: European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16
Agnese Collino: European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16
Shruti Sinha: European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16
Enrico Radaelli: VIB Center for the Biology of Disease, KU Leuven Center for Human Genetics, O&N4 Herestraat 49 box 602
Paola Nicoli: European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16
Lorenzo D’Antiga: Paediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Piazza OMS - Organizzazione Mondiale della Sanità 1
Aurelio Sonzogni: Ospedale Papa Giovanni XXIII, Piazza OMS - Organizzazione Mondiale della Sanità 1
Jamila Faivre: Institut National de la Santé et de la Recherche Médicale (INSERM) U785, University Paris-Sud, France, Centre Hépatobiliaire, Hôpital Paul Brousse
Marie Annick Buendia: Institut National de la Santé et de la Recherche Médicale (INSERM) U785, University Paris-Sud, France, Centre Hépatobiliaire, Hôpital Paul Brousse
Ekkehard Sturm: University Hospital for Children and Adolescents, University of Tuebingen
Richard J. Thompson: Institute of Liver Studies, King's College London
A. S. Knisely: Institute of Liver Studies, King's College Hospital
Gioacchino Natoli: European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16
Serena Ghisletti: European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16
Francesca D. Ciccarelli: European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4850

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