title: Integration of tumour and viral genomic characterizations in HBV-related hepatocellular carcinomas.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is the most common liver cancer. We characterised HCC associated with infection compared with non-HBV-related HCC to understand interactions between viral and hepatocyte genomic alterations and their relationships with clinical features.
  
  
  METHODS
  Frozen HBV (n=86) or non-HBV-related (n=90) HCC were collected in two French surgical departments. Viral characterisation was performed by sequencing HBS and HBX genes and quantifying HBV DNA and cccDNA. Nine genes were screened for somatic mutations and expression profiling of 37 genes involved in hepatocarcinogenesis was studied.
  
  
  RESULTS
  HBX revealed frequent non-sense, frameshift and deletions in tumours, suggesting an HBX inactivation selected in HCC. The number of viral copies was frequently lower in tumour than in non-tumour tissues (p=0.0005) and patients with low HBV copies in the non-tumour liver tissues presented additional risk factor (HCV, alcohol or non-alcoholic steato-hepatitis, p=0.006). P53 was the most frequently altered pathway in HBV-related HCC (47%, p=0.001). Furthermore, TP53 mutations were associated with shorter survival only in HBV-related HCC (p=0.02) whereas R249S mutations were identified exclusively in migrants. Compared with other aetiologies, HBV-HCC were more frequently classified in tumours subgroups with upregulation of genes involved in cell-cycle regulation and a progenitor phenotype. Finally, in HBV-related HCC, transcriptomic profiles were associated with specific gene mutations (HBX, TP53, IRF2, AXIN1 and CTNNB1).
  
  
  CONCLUSIONS
  Integrated genomic characterisation of HBV and non-HBV-related HCC emphasised the immense molecular diversity of HCC closely related to aetiologies that could impact clinical care of HCC patients.
authors.affiliation: Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Amaddeo
authors.affiliation: Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Qian
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Ladeiro
authors.affiliation: Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Imbeaud
authors.affiliation: Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Nault
authors.affiliation: Hypercube research, France.
authors.forename: Daphne
authors.initials: D
authors.lastname: Jaoui
authors.affiliation: Hypercube research, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Gaston Mathe
authors.affiliation: Department of Surgery, CHU de Bordeaux, Bordeaux, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Laurent
authors.affiliation: Assistance Publique-Hôpitaux de Paris, digestive, hepatobiliary and liver transplantation, CHU Henri Mondor, Créteil, France IMRB-Inserm U955 Equipe n. 18 "Virologie moleculaire et immunologie -Physiopathologie et therapeutique des Hépatites virales chroniques", Créteil, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Laurent
authors.affiliation: Inserm, UMR-1053; Université Victor Segalen Bordeaux 2, Bordeaux, France Department of Pathology, CHU de Bordeaux, Pellegrin Hospital, Bordeaux, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.affiliation: Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France Department of Pathology, CHU Henri Mondor, Créteil, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.affiliation: Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France Hopital Europeen Georges Pompidou, Paris, France.
authors.forename: Jessica
authors.identifier: http://orcid.org/0000-0002-5687-0334
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000821:virology*; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000821:virology; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D012307:Risk Factors; D015854:Up-Regulation
chemical_list: D004273:DNA, Neoplasm
keywords: HEPATITIS B; HEPATOCELLULAR CARCINOMA