title: Massive gene amplification drives paediatric hepatocellular carcinoma caused by bile salt export pump deficiency.
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.
authors.affiliation: 1] European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy [2].
authors.forename: Fabio
authors.initials: F
authors.lastname: Iannelli
authors.affiliation: 1] European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy [2].
authors.forename: Agnese
authors.initials: A
authors.lastname: Collino
authors.affiliation: 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].
authors.forename: Shruti
authors.initials: S
authors.lastname: Sinha
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven Center for Human Genetics, O&N4 Herestraat 49 box 602, B-3000 Leuven, Belgium.
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Nicoli
authors.affiliation: Paediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Piazza OMS - Organizzazione Mondiale della Sanità 1, 24128 Bergamo, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: D'Antiga
authors.affiliation: Department of Pathology, Ospedale Papa Giovanni XXIII, Piazza OMS - Organizzazione Mondiale della Sanità 1, 24128 Bergamo, Italy.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Sonzogni
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U785, University Paris-Sud, France, Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif F94800, France.
authors.forename: Jamila
authors.initials: J
authors.lastname: Faivre
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U785, University Paris-Sud, France, Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif F94800, France.
authors.forename: Marie Annick
authors.initials: MA
authors.lastname: Buendia
authors.affiliation: University Hospital for Children and Adolescents, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Sturm
authors.affiliation: Institute of Liver Studies, King's College London, London SE5 9RS, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Thompson
authors.affiliation: Institute of Liver Studies, King's College Hospital, London SE5 9RS, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.affiliation: European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Natoli
authors.affiliation: European Institute of Oncology (IEO), Department of Experimental Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Ghisletti
authors.affiliation: 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.
authors.forename: Francesca D
authors.initials: FD
authors.lastname: Ciccarelli
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002780:Cholestasis, Intrahepatic / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C093491:ABCB11 protein, human