title: Integrated genomic characterization of adrenocortical carcinoma.
abstract: Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland. Despite overall poor prognosis, ACC outcome is heterogeneous. We performed exome sequencing and SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported in ACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77 ACCs. ZNRF3, encoding a cell surface E3 ubiquitin ligase, was the most frequently altered gene (21%) and is a potential new tumor suppressor gene related to the β-catenin pathway. Our integrated genomic analyses further identified two distinct molecular subgroups with opposite outcome. The C1A group of ACCs with poor outcome displayed numerous mutations and DNA methylation alterations, whereas the C1B group of ACCs with good prognosis displayed specific deregulation of two microRNA clusters. Thus, aggressive and indolent ACCs correspond to two distinct molecular entities driven by different oncogenic alterations.
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France. [4] Center for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France. [5].
authors.forename: Guillaume
authors.initials: G
authors.lastname: Assié
authors.affiliation: 1] Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France. [2].
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.affiliation: 1] Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, University of Munich, Munich, Germany. [2] Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany. [3] Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Jouinot
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Windy
authors.initials: W
authors.lastname: Luscap
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France. [4] Center for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Barreau
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Hanin
authors.initials: H
authors.lastname: Omeiri
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Perlemoine
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Fernande
authors.initials: F
authors.lastname: René-Corail
authors.affiliation: Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France.
authors.forename: Nabila
authors.initials: N
authors.lastname: Elarouci
authors.affiliation: 1] Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, University of Munich, Munich, Germany. [2] Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Silviu
authors.initials: S
authors.lastname: Sbiera
authors.affiliation: Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kroiss
authors.affiliation: Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Allolio
authors.affiliation: Visceral, Thoracic and Vascular Surgery, University Hospital Giessen and Marburg, Marburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Waldmann
authors.affiliation: Department of Clinical Endocrinology, Charité Campus Mitte, Charité University Medicine, Berlin, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Quinkler
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mannelli
authors.affiliation: Endocrinology Unit, Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Mantero
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Papathomas
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: De Krijger
authors.affiliation: 1] Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Bordeaux, Bordeaux, France. [2] Rare Adrenal Cancer Network COMETE, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Tabarin
authors.affiliation: 1] Rare Adrenal Cancer Network COMETE, Paris, France. [2] Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Brest, Brest, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Kerlan
authors.affiliation: 1] Rare Adrenal Cancer Network COMETE, Paris, France. [2] Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, Université Paris-Sud, Villejuif, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Baudin
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France. [4] Department of Pathology, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Pierre et Marie Curie Université, Paris, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France. [4] Center for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France. [5] Department of Digestive and Endocrine Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dousset
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France. [4] Center for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.affiliation: Hypertension Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.affiliation: Oncogenetic Laboratory, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Clauser
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France. [4] Center for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France. [5] Rare Adrenal Cancer Network COMETE, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Bruno
authors.identifier: 0000000194764973
authors.initials: B
authors.lastname: Ragazzon
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, University of Munich, Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France. [4] Center for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France. [5] Rare Adrenal Cancer Network COMETE, Paris, France.
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.affiliation: 1] Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France. [2].
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.affiliation: 1] INSERM U1016, Institut Cochin, Paris, France. [2] CNRS UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France. [4] Center for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France. [5] Rare Adrenal Cancer Network COMETE, Paris, France. [6].
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics*; D018268:Adrenocortical Carcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D005810:Multigene Family; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016615:Telomere / Q000648:ultrastructure; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases
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