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Cancer Cell. 2014 Apr 14;25(4):428-41. doi: 10.1016/j.ccr.2014.03.005.

Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation.

Author information

1
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.
2
Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, 75013 Paris, France.
3
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.
4
INSERM, UMR-1053, Université de Bordeaux, 33076 Bordeaux, France.
5
Department of Pathology, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, 75014 Paris, France.
6
Institut Cochin, INSERM U1016, Université Paris Descartes, CNRS UMR8104, 75014 Paris, France.
7
Department of Pathology, Assistance Publique-Hôpitaux de Paris, Beaujon Hospital, Université Paris Diderot, 92210 Clichy, France.
8
Department of Pathology, Edouard Herriot Hospital, 69437 Lyon, France.
9
Department of Hepatogastroenterology, Centre Hospitalier de Tours, Trousseau Hospital, 37044 Tours, France.
10
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.
11
INSERM, UMR-1053, Université de Bordeaux, 33076 Bordeaux, France; Department of Pathology, CHU de Bordeaux, Pellegrin Hospital, 33076, Bordeaux, France.
12
Institut National du Cancer, INCa, 92513 Boulogne, France.
13
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.

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.

PMID:
24735922
DOI:
10.1016/j.ccr.2014.03.005
[Indexed for MEDLINE]
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