Jean-Charles Nault1, Aurélien De Reyniès2, Augusto Villanueva3, Julien Calderaro4, Sandra Rebouissou1, Gabrielle Couchy1, Thomas Decaens5, Dominique Franco6, Sandrine Imbeaud1, Francis Rousseau7, Daniel Azoulay8, Jean Saric9, Jean-Frédéric Blanc10, Charles Balabaud11, Paulette Bioulac-Sage12, Alexis Laurent13, Pierre Laurent-Puig14, Josep M Llovet15, Jessica Zucman-Rossi16. 1. 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. 2. Ligue Nationale Contre le Cancer, Paris, France. 3. 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. 4. 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. 5. 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. 6. AP-HP, Surgery Department, Hôpital Antoine Béclère, Clamart, France. 7. IntegraGen, Evry, France. 8. Université Paris-Est Créteil Val-de-Marne, Créteil, France; Digestive, Hepatobiliary and Liver Transplantation, Assistance Publique-Hôpitaux de Paris, Créteil, France. 9. Department of Surgery, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. 10. Gastroenterology Unit, CHU Bordeaux, Saint André Hôpital, Bordeaux 33075, France. 11. Inserm U1053, Universite Bordeaux Segalen, Bordeaux, France. 12. Inserm U1053, Universite Bordeaux Segalen, Bordeaux, France; Department of Pathology, CHU de Bordeaux, Pellegrin Hospital, Bordeaux, France. 13. 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. 14. Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S775, Paris, France. 15. 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. 16. 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.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: 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: Giacomo Diaz; Ronald E Engle; Ashley Tice; Marta Melis; Stephanie Montenegro; Jaime Rodriguez-Canales; Jeffrey Hanson; Michael R Emmert-Buck; Kevin W Bock; Ian N Moore; Fausto Zamboni; Sugantha Govindarajan; David E Kleiner; Patrizia Farci Journal: Mol Cancer Res Date: 2018-06-01 Impact factor: 5.852