Augusto Villanueva1,2,3, Anna Portela4, Sergi Sayols4,5, Carlo Battiston6, Yujin Hoshida1, Jesús Méndez-González4, Sandrine Imbeaud7,8, Eric Letouzé9, Virginia Hernandez-Gea3, Helena Cornella3, Roser Pinyol3, Manel Solé3, Josep Fuster3, Jessica Zucman-Rossi7,8, Vincenzo Mazzaferro6, Manel Esteller4,10,11, Josep M Llovet1,3,11. 1. Liver Cancer Research Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. 2. Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. 3. Barcelona-Clínic Liver Cancer Group (Liver Cancer Translational Research Laboratory, Liver Unit, Pathology Department, Surgery Department), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBEREHD, Hospital Clínic de Barcelona, Universitat de Barcelona (UB), Barcelona, Spain. 4. Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. 5. Institute of Molecular Biology, Mainz, Germany. 6. Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy. 7. Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France. 8. Université Paris Descartes; Université Paris Diderot, Université Paris 13, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. 9. Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France. 10. Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Spain. 11. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
Abstract
UNLABELLED: Epigenetic deregulation has emerged as a driver in human malignancies. There is no clear understanding of the epigenetic alterations in hepatocellular carcinoma (HCC) and of the potential role of DNA methylation markers as prognostic biomarkers. Analysis of tumor tissue from 304 patients with HCC treated with surgical resection allowed us to generate a methylation-based prognostic signature using a training-validation scheme. Methylome profiling was done with the Illumina HumanMethylation450 array (Illumina, Inc., San Diego, CA), which covers 96% of known cytosine-phosphate-guanine (CpG) islands and 485,000 CpG, and transcriptome profiling was performed with Affymetrix Human Genome U219 Plate (Affymetrix, Inc., Santa Clara, CA) and miRNA Chip 2.0. Random survival forests enabled us to generate a methylation signature based on 36 methylation probes. We computed a risk score of mortality for each individual that accurately discriminated patient survival both in the training (221 patients; 47% hepatitis C-related HCC) and validation sets (n = 83; 47% alcohol-related HCC). This signature correlated with known predictors of poor outcome and retained independent prognostic capacity of survival along with multinodularity and platelet count. The subset of patients identified by this signature was enriched in the molecular subclass of proliferation with progenitor cell features. The study confirmed a high prevalence of genes known to be deregulated by aberrant methylation in HCC (e.g., Ras association [RalGDS/AF-6] domain family member 1, insulin-like growth factor 2, and adenomatous polyposis coli) and other solid tumors (e.g., NOTCH3) and describes potential candidate epidrivers (e.g., septin 9 and ephrin B2). CONCLUSIONS: A validated signature of 36 DNA methylation markers accurately predicts poor survival in patients with HCC. Patients with this methylation profile harbor messenger RNA-based signatures indicating tumors with progenitor cell features.
UNLABELLED: Epigenetic deregulation has emerged as a driver in humanmalignancies. There is no clear understanding of the epigenetic alterations in hepatocellular carcinoma (HCC) and of the potential role of DNA methylation markers as prognostic biomarkers. Analysis of tumor tissue from 304 patients with HCC treated with surgical resection allowed us to generate a methylation-based prognostic signature using a training-validation scheme. Methylome profiling was done with the Illumina HumanMethylation450 array (Illumina, Inc., San Diego, CA), which covers 96% of known cytosine-phosphate-guanine (CpG) islands and 485,000 CpG, and transcriptome profiling was performed with Affymetrix Human Genome U219 Plate (Affymetrix, Inc., Santa Clara, CA) and miRNA Chip 2.0. Random survival forests enabled us to generate a methylation signature based on 36 methylation probes. We computed a risk score of mortality for each individual that accurately discriminated patient survival both in the training (221 patients; 47% hepatitis C-related HCC) and validation sets (n = 83; 47% alcohol-related HCC). This signature correlated with known predictors of poor outcome and retained independent prognostic capacity of survival along with multinodularity and platelet count. The subset of patients identified by this signature was enriched in the molecular subclass of proliferation with progenitor cell features. The study confirmed a high prevalence of genes known to be deregulated by aberrant methylation in HCC (e.g., Ras association [RalGDS/AF-6] domain family member 1, insulin-like growth factor 2, and adenomatous polyposis coli) and other solid tumors (e.g., NOTCH3) and describes potential candidate epidrivers (e.g., septin 9 and ephrin B2). CONCLUSIONS: A validated signature of 36 DNA methylation markers accurately predicts poor survival in patients with HCC. Patients with this methylation profile harbor messenger RNA-based signatures indicating tumors with progenitor cell features.
Authors: Raquel Ordoñez; Anna Fernández; Néstor Prieto-Domínguez; Laura Martínez; Carmen García-Ruiz; José C Fernández-Checa; José L Mauriz; Javier González-Gallego Journal: J Pineal Res Date: 2015-06-08 Impact factor: 13.007
Authors: Victoria Tovar; Helena Cornella; Agrin Moeini; Samuel Vidal; Yujin Hoshida; Daniela Sia; Judit Peix; Laia Cabellos; Clara Alsinet; Sara Torrecilla; Iris Martinez-Quetglas; Juan José Lozano; Christèle Desbois-Mouthon; Manel Solé; Josep Domingo-Domenech; Augusto Villanueva; Josep M Llovet Journal: Gut Date: 2015-12-11 Impact factor: 23.059