title: Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation.
abstract: Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications.
  
  
  
  We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation.
  
  
  
  Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with β-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively.
  
  
  
  Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.
authors.affiliation: Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Université Paris Diderot, Paris, France; Liver Unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance Publique Hôpitaux de Paris, Bondy, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Nault
authors.affiliation: Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Université Paris Diderot, Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.affiliation: Université Bordeaux, Bordeaux Research in Translational Oncology, Bordeaux, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.affiliation: Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Université Paris Diderot, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Morcrette
authors.affiliation: Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Université Paris Diderot, Paris, France.
authors.forename: Stefano
authors.initials: S
authors.lastname: Caruso
authors.affiliation: Université Bordeaux, Bordeaux Research in Translational Oncology, Bordeaux, France; Service Hépato-Gastroentérologie et Oncologie Digestive, Centre Medico-Chirurgical Magellan, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Jean-Frederic
authors.initials: JF
authors.lastname: Blanc
authors.affiliation: Service d'Hépatogastroentérologie, Centre Hospitalier Régional Universitaire de Tours, Tours, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Bacq
authors.affiliation: Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Université Paris Diderot, Paris, France; Service d'Anatomopathologie, Hôpital Henri Mondor, Université Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale U955, Institut Mondor de Recherche Biomédicale, Créteil, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.affiliation: Service d'Anatomopathologie, Hôpital Beaujon, Clichy, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Paradis
authors.affiliation: Service d'Anatomopathologie, Gui de Chauliac, Montpellier, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Ramos
authors.affiliation: Service d'Anatomopathologie, Institut Gustave Roussy, Villejuif, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: Institut de Pathologie, Centre Hospitalier Régional Universitaire de Lille, UMR-S 1124, Jean-Pierre Aubert Research Center, Lille, France.
authors.forename: Viviane
authors.initials: V
authors.lastname: Gnemmi
authors.affiliation: Service d'Anatomopathologie, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sturm
authors.affiliation: Service d'Anatomopathologie, Hôpitaux Paul Brousse et Bicêtre, Le Kremlin Bicêtre, Institut National de la Santé et de la Recherche Médicale U1193 Université Paris-Sud, Orsay, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.affiliation: Service d'Anatomopathologie, Hôptal Necker-Enfants Malades, Paris, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Fabre
authors.affiliation: Service de Chirurgie Hépato-Bilio-Pancréatique, Centre Hospitalier Universitaire, Pitié Salpétrière, Université Pierre et Marie Curie, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Savier
authors.affiliation: Service de Chirurgie Digestive, Centre Medico-Chirurgical Magellan, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire Bordeaux, Bordeaux, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Chiche
authors.affiliation: Assistance Hôpitaux Publique de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Antoine Béclère, Centre de Référence des Maladies Héréditaires du Métabolisme Hépatique, Clamart, and Université Paris-Sud, and Institut National de la Santé et de la Recherche Médicale U 1169, Orsay, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Labrune
authors.affiliation: Département d'Anatomopathologie, Institut Universitaire du Cancer-Oncopole, Toulouse, France.
authors.forename: Janick
authors.initials: J
authors.lastname: Selves
authors.affiliation: Service d'Anatomie Pathologique, Assistance Hôpitaux Publique de Paris Hôpital St Antoine, Sorbonne Universités, Université Pierre et Marie Curie 06, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Wendum
authors.affiliation: Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Université Paris Diderot, Paris, France.
authors.forename: Camilla
authors.initials: C
authors.lastname: Pilati
authors.affiliation: Service de Chirurgie Digestive, Hôpital Henri Mondor, Créteil, Institut National de la Santé et de la Recherche Médicale U955, Créteil, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Laurent
authors.affiliation: Service d'anatomopathologie, Centre Hospitalier Régional Universitaire de Tours, Tours, France.
authors.forename: Anne
authors.initials: A
authors.lastname: De Muret
authors.affiliation: Université Bordeaux, Bordeaux Research in Translational Oncology, Bordeaux, France; Service de Pathologie, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Le Bail
authors.affiliation: Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Université Paris Diderot, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rebouissou
authors.affiliation: Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Université Paris Diderot, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Imbeaud
authors.affiliation: Université Bordeaux, Bordeaux Research in Translational Oncology, Bordeaux, France; Service de Pathologie, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.affiliation: Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Université Paris Diderot, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.affiliation: Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Université Paris Diderot, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Département d'Oncologie, Paris, France. Electronic address: jessica.zucman-rossi@inserm.fr.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D000236:Adenoma / Q000737:chemistry / Q000145:classification / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D002864:Chromogranins / Q000235:genetics; D050822:Cytokine Receptor gp130 / Q000235:genetics; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D050939:Gene Fusion; D053823:Hedgehog Proteins / Q000378:metabolism; D006470:Hemorrhage / Q000209:etiology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics*; D053614:Janus Kinase 2 / Q000235:genetics; D008113:Liver Neoplasms / Q000737:chemistry / Q000145:classification / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D012307:Risk Factors; D050796:STAT3 Transcription Factor / Q000235:genetics; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics; D059467:Transcriptome; D055815:Young Adult; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
chemical_list: C495270:CTNNB1 protein, human; D002864:Chromogranins; C400551:GLI1 protein, human; C496487:HNF1A protein, human; D053823:Hedgehog Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C494199:IL6ST protein, human; C504183:INHBE protein, human; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin; D050822:Cytokine Receptor gp130; D028322:Inhibin-beta Subunits; D011505:Protein-Tyrosine Kinases; C092830:FRK protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C509186:TERT protein, human; D019098:Telomerase; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: Benign; HCC; SHH; Tumor Progression