title: Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation.
abstract: Hepatocellular adenomas (HCA) are benign liver tumors predominantly developed in women using oral contraceptives. Here, exome sequencing identified recurrent somatic FRK mutations that induce constitutive kinase activity, STAT3 activation, and cell proliferation sensitive to Src inhibitors. We also found uncommon recurrent mutations activating JAK1, gp130, or β-catenin. Chromosome copy number and methylation profiling revealed patterns that correlated with specific gene mutations and tumor phenotypes. Finally, integrative analysis of HCAs transformed to hepatocellular carcinoma revealed β-catenin mutation as an early alteration and TERT promoter mutations as associated with the last step of the adenoma-carcinoma transition. In conclusion, we identified the genomic diversity in benign hepatocyte proliferation, several therapeutic targets, and the key genomic determinants of the adenoma-carcinoma transformation sequence.
authors.affiliation: INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.
authors.forename: Camilla
authors.initials: C
authors.lastname: Pilati
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, 75013 Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.affiliation: INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Nault
authors.affiliation: INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Imbeaud
authors.affiliation: INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Boulai
authors.affiliation: INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France; Department of Pathology, Assistance Publique-Hôpitaux de Paris, CHU Henri Mondor, 94000 Créteil, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.affiliation: INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Poussin
authors.affiliation: INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Franconi
authors.affiliation: INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.affiliation: INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Morcrette
authors.affiliation: INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Mallet
authors.affiliation: INSERM, UMR-1053, Université de Bordeaux, 33076 Bordeaux, France.
authors.forename: Saïd
authors.initials: S
authors.lastname: Taouji
authors.affiliation: INSERM, UMR-1053, Université de Bordeaux, 33076 Bordeaux, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.affiliation: Department of Pathology, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, 75014 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Terris
authors.affiliation: Institut Cochin, INSERM U1016, Université Paris Descartes, CNRS UMR8104, 75014 Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Canal
authors.affiliation: Department of Pathology, Assistance Publique-Hôpitaux de Paris, Beaujon Hospital, Université Paris Diderot, 92210 Clichy, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Paradis
authors.affiliation: Department of Pathology, Edouard Herriot Hospital, 69437 Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: Department of Hepatogastroenterology, Centre Hospitalier de Tours, Trousseau Hospital, 37044 Tours, France.
authors.forename: Anne
authors.initials: A
authors.lastname: de Muret
authors.affiliation: Department of Pathology, Assistance Publique-Hôpitaux de Paris, CHU Bicêtre, 94275 Le Kremlin-Bicêtre, France; Department of Pathology, Assistance Publique-Hôpitaux de Paris, CHU Paul Brousse, 94800 Villejuif, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.affiliation: INSERM, UMR-1053, Université de Bordeaux, 33076 Bordeaux, France; Department of Pathology, CHU de Bordeaux, Pellegrin Hospital, 33076, Bordeaux, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.affiliation: INSERM, UMR-1053, Université de Bordeaux, 33076 Bordeaux, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
authors.affiliation: Institut National du Cancer, INCa, 92513 Boulogne, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Calvo
authors.affiliation: INSERM, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, 75010 Paris, France; Labex Immuno-oncology, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, 75015 Paris, France. Electronic address: jessica.zucman-rossi@inserm.fr.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D018248:Adenoma, Liver Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D014162:Transfection
chemical_list: D009363:Neoplasm Proteins; D011505:Protein-Tyrosine Kinases; C092830:FRK protein, human