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Molecular Classification of Hepatocellular Adenoma

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Molecular Classification of Hepatocellular Adenoma Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation Jean-Charles Nault, Gabrielle Couchy, Charles Balabaud, Guillaume Morcrette, Stefano Caruso, Jean-Frederic Blanc, Yannick Bacq, Julien Calderaro, Valérie Paradis, Jeanne Ramos, et al. To cite this version: Jean-Charles Nault, Gabrielle Couchy, Charles Balabaud, Guillaume Morcrette, Stefano Caruso, et al.. Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation. Gastroenterology, WB Saunders, 2017, 152 (4), pp.880 - 894.e6. 10.1053/j.gastro.2016.11.042. hal-01797602 HAL Id: hal-01797602 https://hal.archives-ouvertes.fr/hal-01797602 Submitted on 16 Jan 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Gastroenterology Molecular Classification of Hepatocellular Adenoma: Interactions with Risk Factors and Clinical Outcomes --Manuscript Draft-- Manuscript Number: GASTRO-D-16-02075R1 Full Title: Molecular Classification of Hepatocellular Adenoma: Interactions with Risk Factors and Clinical Outcomes Article Type: Basic - Liver Section/Category: Basic Corresponding Author: Jessica Zucman-Rossi, M.D., PhD INSERM Paris, P FRANCE Corresponding Author Secondary Information: Corresponding Author's Institution: INSERM Corresponding Author's Secondary Institution: First Author: Jean-Charles Nault First Author Secondary Information: Order of Authors: Jean-Charles Nault Gabrielle Couchy Charles Balabaud Guillaume Morcrette Stefano Caruso Jean Frederic Blanc Yannick Bacq Julien Calderaro Valérie Paradis Jeanne Ramos Jean-Yves Scoazec Viviane Gnemmi Nathalie Sturm Catherine Guettier Monique Fabre Eric Savier Laurence Chiche Philippe Labrune Janick Selves Dominique Wendum Camilla Pilati Alexis Laurent Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Anne De Muret Brigitte Lebail Sandra Rebouissou Sandrine Imbeaud Paulette Bioulac-Sage Eric Letouze Jessica Zucman-Rossi, M.D., PhD Order of Authors Secondary Information: Abstract: Background and Aims Hepatocellular adenomas (HCA) are benign liver tumors divided in molecular subtypes characterized by mutations inactivating HNF1A, activating β-catenin or inflammatory pathway. We aimed to refine HCA natural history according to an updated molecular classification. Methods 607 samples of 533 HCA from 411 patients collected in 28 centers were systematically analyzed by expression profiling and sequencing 20 and 8 genes, respectively. Microarray analysis, RNA sequencing, whole-exome and genome sequencing were performed in selected cases. Clinical and pathological features were compared with molecular data. Results Symptomatic bleeding occurred in 14% of the patients (female 85%, median age 38 y), 7% of the nodules were borderline between adenoma and carcinoma (HCA/HCC) and in 3% HCC developed on HCA. We defined a new molecular classification of HCA in 8 molecular subgroups. Among them, we identified a new HCA subgroup (4%, previously unclassified) associated with obesity and bleeding. These tumors were characterized by a sonic Hedgehog pathway activation due to focal deletions creating INHBE promoter/GLI1 fusions. Analysis of inter-tumor genetic heterogeneity of multiple HCA in patients revealed a "molecular subtype field effect" with tumors harboring private mutations leading to similar pathway deregulation. Specific molecular HCA subtypes were associated with various risk factors and estrogen/androgen hormonal balances. Finally, the molecular classification enabled to stratify patients according to the risk of bleeding and malignant transformation. Conclusion INHBE-GLI1 fusion defined a new subgroup of HCA characterized by sonic hedgehog activation. Molecular classification identified subgroups of patients related to specific risk factors, clinical behavior and pathological features laying the foundations for personalized treatment. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Revised Manuscript in Word or RTF (with changes marked) Molecular Classification of Hepatocellular Adenoma: Interactions with Risk Factors and Clinical Outcomes Short title: molecular classification of liver adenomas Jean Charles Nault1, 2, 3, Gabrielle Couchy 1, Charles Balabaud4, Guillaume Morcrette 1, Stefano Caruso1, Jean-Frederic Blanc4,5, Yannick Bacq6, Julien Calderaro1,7, Valeérie Paradis8, Jeanne Ramos9, Jean-Yves Scoazec10, Viviane Gnemmi11, Nathalie Sturm12, Catherine Guettier13, Monique Fabre14, Eric Savier15, Laurence Chiche16, Philippe Labrune17, Janick Selves 18, Dominique Wendum 19, Camilla Pilati 1, Alexis Laurent 20, Anne De Muret21, Brigitte Le Bail4,22, Sandra Rebouissou1, Sandrine Imbeaud1, GENTHEP investigators, Paulette Bioulac-Sage 4, 22, Eric Letouzeé 1, Jessica Zucman-Rossi1 1. Uniteé Mixte de Recherche 1162, Geénomique fonctionnelle des tumeurs solides, Institut National de la Santeé et de la Recherche Meédicale, Paris, France. 2. Liver unit, Hoôpital Jean Verdier, Hoôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance- Publique Hoôpitaux de Paris, Bondy, France 3. Uniteé de Formation et de Recherche Santeé Meédecine et Biologie Humaine, Universiteé Paris 13, Communauteé d’Universiteés et Etablissements Sorbonne Paris Citeé, Paris, France 4. Univ. Bordeaux, UMR1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France 5. Service Heépato-Gastroenteérologie et oncologie digestive, Centre Medico-Chirurgical Magellan, Hoôpital Haut-Leéveôque, CHU de Bordeaux, F 33000 Bordeaux France 6. Service d’heépatogastroenteérologie, CHRU de Tours, Tours 7. Service d’anatomopathologie, Hoôpital Henri Mondor, Creéteil ; Universiteé Paris Est Creéteil, Inserm U955, Team 18, Institut Mondor de Recherche Biomeédicale 8. Service d’anatomopathologie, Hoôpital Beaujon, Clichy 9. Service d’anatomopathologie, Gui de Chauliac, Montpellier 10. Service d’anatomopathologie, Institut Gustave Roussy, Villejuif 11. Institut de Pathologie. CHRU de Lille.UMR-S 1172 - JPARC - Jean-Pierre Aubert Research Center, F-59000 Lille, France 12. Service d’anatomopathologie, CHU de Grenoble 13. Service d’anatomopathologie, Hoôpitaux Paul Brousse et Biceôtre, Le Kremlin Biceôtre INSERM U 1193 Univ Paris Sud 14. Service d’anatomopathologie, Hoôptal Necker-Enfants Malades, Paris 15. Service de chirurgie heépato-bilio-pancreéatique, CHU Pitieé Salpeétrieère, Univ. Pierre et Marie Curie UPMC, Paris 16. Service de chirurgie digestive, Centre Medico-Chirurgical Magellan, Hoôpital Haut-Leéveôque, CHU Bordeaux 17. APHP, Hoôpitaux Universitaires Paris Sud, Hoôpital Antoine Beécleère, Centre de Reéfeérence des Maladies Heéreéditaires du Meétabolisme Heépatique, Clamart, and Univ- Paris Sud, and INSERM U 1169, France 18. Deépartement d’anatomopathologie, Institut Universitaire du Cancer-Oncopole, Toulouse, France 19. Service d’Anatomie Pathologique, APHP Hoôpital St Antoine, Sorbonne Universiteés, UPMC Univ Paris 06, Paris, France 20. Service de chirurgie digestive, Hoôpital Henri Mondor, Creéteil. Inserm U955 – Team 18 – Creéteil France 21. Service d’anatomopathologie, CHRU de Tours 22. Service de Pathologie, Hoôpital Pellegrin, CHU de Bordeaux, F 33000 Bordeaux France Grants supports: ARC (2003), SNFGE (2005), Inca (2006), GENTHEP Inserm network (2003-2008), Equipe Labelliseée Ligue contre le cancer, Labex OncoImmunlogy investissement d’avenir. the French Liver Biobanks network – INCa, BB-0033-00085, Hepatobio bank. Abbreviations : AP: alkaline phosphatase, b ex7,8HCA: β-catenin mutated hepatocellular adenoma in exon 7 or 8, bex7,8IHCA : β-catenin mutated inflammatory hepatocellular adenoma in exon 7 or 8, bex3IHCA: β-catenin mutated inflammatory hepatocellular adenoma in exon 3, bex3HCA: β-catenin mutated hepatocellular adenoma in exon 3, BMI: body mass index, CTNNB1 : cadherin-associated protein beta 1, FRK : fyn related kinase, GLI1 : Glioma- Associated Oncogene 1, GNAS : Guanine Nucleotide Binding Protein Alpha Stimulating,, GGT: Gamma Glutamyl Transferase, HCA : hepatocellular adenoma, HCC : hepatocellular carcinoma, HHCA : HNF1A mutated hepatocellular adenoma, HNF1A : hepatocyte nuclear factor 1A, IL-6 : Interleukin 6, IHCA : inflammatory hepatocellular adenoma, INHBE : Inhibin Beta E, JAK : Janus Kinase, MRI: magnetic resonance imaging, OC: oral contraception, PTCH1: Patched Homolog 1, shHCA : sonic hedgehog hepatocellular adenoma, SMO: Smoothened, STAT : Signal transducer and activator of transcription , SUFU: Suppressor Of Fused Homolog, TERT : telomerase reverse transcriptase, UHCA : unclassified hepatocellular adenoma, WES: whole-exome sequencing, WGS: whole genome sequencing. Correspondence: Jessica Zucman-Rossi; MD, PhD INSERM U 1162, Geénomique fonctionnelle des tumeurs solides 27 Rue Juliette Dodu 75010 Paris, France TEL: +33 1 53 72 51 66 FAX: +33 1 53 72 51 92 Email: [email protected] Conflict of interests for all authors: the authors have no conflicts of interests related to the manuscript, none to declare. Transcripts profiling: accessions EGAS00001002091,
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