title: A hepatocellular carcinoma 5-gene score associated with survival of patients after liver resection.
abstract: OBJECTIVE
  Due to the phenotypic and molecular diversity of hepatocellular carcinomas (HCC), it is a challenge to determine a patient's prognosis. We aimed to identify new prognostic markers of patients with HCC treated by liver resection.
  
  
  METHODS
  We collected 314 HCC samples from patients at Bordeaux (1998-2007) and Créteil (2003-2007) hospitals in France. We analyzed the gene expression patterns of the tumors and compared expression patterns with patient survival times. Using the coefficient and regression formula of the multivariate Cox model, we identified a "5-gene score" associated with survival times. This molecular score was then validated in 2 groups of patients from Europe and the United States (n = 213) and China (n = 221).
  
  
  RESULTS
  The 5-gene score, based on combined expression level of HN1, RAN, RAMP3, KRT19, and TAF9, was associated with disease-specific survival times of 189 patients with resected HCC in Bordeaux (hazard ratio = 3.5; 95% confidence interval: 1.9-6.6; P < .0001). The association between the 5-gene score and disease-specific survival was validated in an independent cohort of 125 patients in Créteil (hazard ratio = 2.3; 95% confidence interval: 1.1-4.9; P < .0001). The 5-gene score more accurately predicted patient outcomes than gene expression signatures reported previously. In multivariate analyses, the 5-gene score was associated with disease-specific survival, independent of other clinical and pathology feature of HCC. Disease-specific survival was also predicted by combining data on microvascular invasion, the Barcelona Clinic Liver Cancer classification system, and the 5-gene score in a nomogram. The prognostic accuracy of the 5-gene score was further validated in European and US patients with hepatitis C, cirrhosis, and HCC (overall survival P = .002) and in Asian patients with HCC with hepatitis B (overall survival, P = .02). Combining the 5-gene score with the expression pattern of 186 genes in corresponding cirrhotic tissues increased its prognostic accuracy.
  
  
  CONCLUSIONS
  The molecular 5-gene score is associated with outcomes of patients with HCC treated by resection in different clinical settings worldwide. This new biomarker should be tested in clinical trials to stratify patients in therapeutic decisions.
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: Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: De Reyniès
authors.affiliation: HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Liver Unit, Hospital Clinic, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto Carlos III, Barcelona, Spain.
authors.forename: Augusto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Inserm, UMR-674, Génomique Fonctionnelle des Tumeurs Solides, IUH, Paris, France; AP-HP, Department of Pathology, Henri Mondor University Hospital, Créteil, France; Université Paris-Est Créteil Val-de-Marne, 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rebouissou
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: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.affiliation: AP-HP, Department of Hepatology, Henri Mondor University Hospital, Créteil, France; Université Paris-Est Créteil Val-de-Marne, Créteil, France; Inserm U955, Pathophysiology and Therapy of Chronic Viral Hepatitis, Créteil, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Decaens
authors.affiliation: AP-HP, Surgery Department, Hôpital Antoine Béclère, Clamart, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Franco
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: IntegraGen, Evry, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: Université Paris-Est Créteil Val-de-Marne, Créteil, France; Digestive, Hepatobiliary and Liver Transplantation, Assistance Publique-Hôpitaux de Paris, Créteil, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Azoulay
authors.affiliation: Department of Surgery, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Saric
authors.affiliation: Gastroenterology Unit, CHU Bordeaux, Saint André Hôpital, Bordeaux 33075, France.
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Blanc
authors.affiliation: Inserm U1053, Universite Bordeaux Segalen, Bordeaux, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.affiliation: Inserm U1053, Universite Bordeaux Segalen, Bordeaux, France; Department of Pathology, CHU de Bordeaux, Pellegrin Hospital, Bordeaux, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.affiliation: Université Paris-Est Créteil Val-de-Marne, Créteil, France; Inserm U955, Pathophysiology and Therapy of Chronic Viral Hepatitis, Créteil, France; Digestive, Hepatobiliary and Liver Transplantation, Assistance Publique-Hôpitaux de Paris, Créteil, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Laurent
authors.affiliation: Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S775, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Liver Unit, Hospital Clinic, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto Carlos III, Barcelona, Spain; Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Mount Sinai School of Medicine, New York, New York; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
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; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. Electronic address: zucman@cephb.fr.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D018797:Cell Cycle Proteins; D005260:Female; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D008297:Male; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins; D011379:Prognosis; D016016:Proportional Hazards Models; D058264:Receptor Activity-Modifying Protein 3 / Q000235:genetics; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics; D035362:Transcription Factor TFIID / Q000235:genetics; D020931:ran GTP-Binding Protein / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C572206:JPT1 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C545504:RAMP3 protein, human; C120587:RAN protein, human; D058264:Receptor Activity-Modifying Protein 3; C106849:TAF9 protein, human; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D020931:ran GTP-Binding Protein