Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. ; Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.: Transcriptome and HCC classification
In: ISSN: 0270-9139, 2007
Online
academicJournal
Zugriff:
Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. We further investigated transcriptome-genotype-phenotype correlations in HCC. Global transcriptome analyses were performed on 57 HCCs and 3 hepatocellular adenomas and validated by quantitative RT-PCR using 63 additional HCCs. We determined loss of heterozygosity, gene mutations, promoter methylation of CDH1 and CDKN2A, and HBV DNA copy number for each tumor. Unsupervised transcriptome analysis identified 6 robust subgroups of HCC (G1-G6) associated with clinical and genetic characteristics. G1 tumors were associated with low copy number of HBV and overexpression of genes expressed in fetal liver and controlled by parental imprinting. G2 included HCCs infected with a high copy number of HBV and mutations in PIK3CA and TP53. In these first groups, we detected specific activation of the AKT pathway. G3 tumors were typified by mutation of TP53 and overexpression of genes controlling the cell cycle. G4 was a heterogeneous subgroup of tumors including TCF1-mutated hepatocellular adenomas and carcinomas. G5 and G6 were strongly related to beta-catenin mutations that lead to Wnt pathway activation; in particular, G6 tumors were characterized by satellite nodules, higher activation of the Wnt pathway, and E-cadherin underexpression. CONCLUSION: These results have furthered our understanding of the genetic diversity of human HCC and have provided specific identifiers for classifying tumors. In addition, our classification has potential therapeutic implications because 50% of the tumors were related to WNT or AKT pathway activation, which potentially could be targeted by specific inhibiting therapies.
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Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. ; Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.: Transcriptome and HCC classification
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Autor/in / Beteiligte Person: | Boyault, Sandrine ; Rickman, David, S. ; de Reyniès, Aurélien ; Balabaud, Charles ; Rebouissou, Sandra ; Jeannot, Emmanuelle ; Hérault, Aurélie ; Saric, Jean ; Belghiti, Jacques ; Franco, Dominique ; Bioulac-Sage, Paulette ; Laurent-Puig, Pierre ; Zucman-Rossi, Jessica ; Génomique Fonctionnelle des Tumeurs Solides (U1162) ; Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Institut Universitaire d'Hématologie (IUH) ; Université Paris Diderot - Paris 7 (UPD7) ; Département de Bioinformatique ; Ligue Nationale Contre le Cancer (LNCC) ; Fibrose hépatique et cancer du foie ; Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM) ; d'Hépato-Gastro-Entérologie, Service ; CHU Bordeaux-Hôpital Saint-André ; Service de chirurgie digestive ; Service de chirurgie ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon AP-HP ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) ; Centre de chirurgie ambulatoire Béclère ; Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère Clamart ; Laboratoire d'anatomie pathologique ; CHU Bordeaux-Groupe hospitalier Pellegrin ; Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)) ; Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; We warmly thank Jacqueline Godet, François Sigaux and Philippe Dessen managers of the Carte d'Identité des Tumeurs (CIT) program founded by the Ligue Nationale contre le Cancer ; Daniela Geromin, Christelle Thibault, Patricia Legoix, Damien Gerald, Olivier Bluteau, for their experimental help ; Fabien Petel for his help in the submission of the data to, EBI ; Philippe Bois for critical reading of the manuscript. We thank the technicians from the CEPH, Fondation Jean Dausset for their help in sequencing and all the clinicians that referred the patients. This work was supported by the Ligue Nationale Contre le Cancer and the Fondation de France. SB, SR and EJ are supported by a Fondation de France, a Ligue Nationale Contre le Cancer and a Association pour la Recherche sur le Cancer grant fellowship, respectively. |
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Zeitschrift: | ISSN: 0270-9139, 2007 |
Veröffentlichung: | HAL CCSD ; Wiley-Blackwell, 2007 |
Medientyp: | academicJournal |
DOI: | 10.1002/hep.21467 |
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