Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/110932
Title: DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma
Author: Villanueva, Augusto
Portela, Anna
Sayols, Sergi
Battiston, Carlo
Hoshida, Yujin
Méndez-González, Jesús
Imbeaud, Sandrine
Letouzé, Eric
Hernandez-Gea, Virginia
Cornella, Helena
Pinyol, Roser
Solé Arqués, Manuel
Fuster Obregón, Josep
Zucman-Rossi, Jessica
Mazzaferro, Vincenzo
Esteller, Manel
Llovet i Bayer, Josep Maria
HEPTROMIC Consortium
Keywords: Càncer de fetge
Metilació
ADN
Epigènesi
Pronòstic mèdic
Liver cancer
Methylation
DNA
Epigenesis
Prognosis
Issue Date: Jun-2015
Publisher: Wiley
Abstract: 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.
Note: Versió postprint del document publicat a: https://doi.org/10.1002/hep.27732
It is part of: Hepatology, 2015, vol. 61, num. 6, p. 1945-1956
Related resource: https://doi.org/10.1002/hep.27732
URI: http://hdl.handle.net/2445/110932
ISSN: 0270-9139
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Cirurgia i Especialitats Medicoquirúrgiques)
Articles publicats en revistes (Medicina)
Publicacions de projectes de recerca finançats per la UE
Articles publicats en revistes (Fonaments Clínics)

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