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Gastroenterology. 2015 Oct;149(5):1226-1239.e4. doi: 10.1053/j.gastro.2015.05.061. Epub 2015 Jun 20.

Genetic Landscape and Biomarkers of Hepatocellular Carcinoma.

Author information

1
Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France; Université Paris Diderot, Paris. Electronic address: jessica.zucman-rossi@inserm.fr.
2
Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
3
Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Service d'hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.
4
Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Liver Unit, CIBEREHD, Hospital Clínic, Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain. Electronic address: jmllovet@clinic.cat.

Abstract

Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortality has increased in Western populations, with a minority of patients diagnosed at early stages, when curative treatments are feasible. Only the multikinase inhibitor sorafenib is available for the management of advanced cases. During the last 10 years, there has been a clear delineation of the landscape of genetic alterations in HCC, including high-level DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), as well as homozygous deletions in chromosome 9 (CDKN2A). The most frequent mutations affect TERT promoter (60%), associated with an increased telomerase expression. TERT promoter can also be affected by copy number variations and hepatitis B DNA insertions, and it can be found mutated in preneoplastic lesions. TP53 and CTNNB1 are the next most prevalent mutations, affecting 25%-30% of HCC patients, that, in addition to low-frequency mutated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of the core deregulated pathways in HCC. Conceptually, some of these changes behave as prototypic oncogenic addiction loops, being ideal biomarkers for specific therapeutic approaches. Data from genomic profiling enabled a proposal of HCC in 2 major molecular clusters (proliferation and nonproliferation), with differential enrichment in prognostic signatures, pathway activation and tumor phenotype. Translation of these discoveries into specific therapeutic decisions is an unmet medical need in this field.

KEYWORDS:

Genomics; Liver Cancer; Molecular Therapies; Signaling Pathways

PMID:
26099527
DOI:
10.1053/j.gastro.2015.05.061
[Indexed for MEDLINE]

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