title: Germline and somatic DICER1 mutations in familial and sporadic liver tumors.
abstract: Growing evidence suggests that genetic predisposition significantly increases the risk of hepatocellular carcinoma (HCC), independently from the presence of other risk factors. Here, we report a novel germline DICER1 mutation associated with familial recurrent liver tumors. We then aimed to investigate the contribution of constitutional and somatic DICER1 mutations on HCC occurrence.
  
  
  
  We investigated two individuals of a single family that developed recurrent well-differentiated hepatocellular tumors over the years. Histological slides from surgically resected tumors were reviewed. Exome sequencing was performed on constitutional DNA from circulating lymphocytes in both patients. The presence of somatic DICER1 mutations was analyzed in 243 liver tumors. MicroRNA (miRNA) sequencing was performed in 50 liver tumors to identify groups of tumors with similar profiles and differentially expressed miRNAs (DEMs).
  
  
  
  A pathological study identified hepatocellular adenomas and well-differentiated carcinomas in both patients. Tumors exhibited Wnt/β-catenin pathway activation, with strong and diffuse glutamine synthetase expression. Interestingly, non-tumor liver tissues showed abnormal liver zonation as previously reported in Dicer1 knockout mouse livers. Screening for DICER1 mutations in 243 sporadic liver tumors identified six tumors with somatic DICER1 mutations. In HCCs, DICER1 mutations were significantly associated with CTNNB1 mutations (p=0.03). miRNA profiling identified a specific expression profile in DICER1-mutated tumors with a decreased expression of mature miRNAs compared to the other samples. Among the DEMs, downregulation of let-7a and miR-365b was closely related to DICER1 mutations.
  
  
  
  Our results highlight the role of DICER1 mutations in liver carcinogenesis in a specific subtype of familial and sporadic hepatocellular carcinomas associated with β-catenin activation.
  
  
  
  DICER1 germline mutations are known to predispose individuals to the development of malignant tumors, mainly pleuropulmonary blastoma and ovarian Sertoli-Leydig cell tumor. Here, we described familial HCC associated with a novel DICER1 germline mutation and altered liver zonation. Familial and sporadic HCCs carrying DICER1 mutations are associated with CTNNB1 mutation and characterized by a reduced expression of specific mature miRNAs.
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France; Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Stefano
authors.initials: S
authors.lastname: Caruso
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; AP-HP, Department of Pathology, CHU Henri Mondor, Créteil, France; Université Paris-Est Créteil, 94010 Créteil, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France; Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France; Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France; AP-HP, Hôpitaux Universitaires Paris-Seine Saint-Denis, Site Jean Verdier, Pôle d'Activité Cancérologique Spécialisée, Service d'Hépatologie, Bondy, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Nault
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France; Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France; Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Boulai
authors.affiliation: AP-HP, Department of Medical Imaging, CHU Henri Mondor, Créteil, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Luciani
authors.affiliation: AP-HP, Department of Pathology, CHU Henri Mondor, Créteil, France.
authors.forename: Elie-Serge
authors.initials: ES
authors.lastname: Zafrani
authors.affiliation: INSERM, UMR 1053, Bordeaux, France; Université de Bordeaux, Bordeaux, France; CHU de Bordeaux, Pellegrin Hospital, Department of Pathology, Bordeaux, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; AP-HP, Radiology Department, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Bondy, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Seror
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France; Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Imbeaud
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche (UFR) Santé, Médecine, Biologie Humaine (SMBH), Bobigny, France; Université Paris Diderot, Institut Universitaire d'Hématologie, Paris, France; AP-HP, Hôpital Européen Georges Pompidou, Paris, France. Electronic address: jessica.zucman-rossi@inserm.fr.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D012334:RNA, Neoplasm / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics*; D059467:Transcriptome; D051176:beta Catenin / Q000235:genetics
chemical_list: C495270:CTNNB1 protein, human; C546819:MIRN365 microRNA, human; D035683:MicroRNAs; D012334:RNA, Neoplasm; D051176:beta Catenin; C487931:mirnlet7 microRNA, human; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: Beta-catenin; DICER1; Familial tumors; Germline mutation; Hepatocellular carcinoma; Liver; Somatic mutation; Zonation; microRNAs