Genetic Landscape and Biomarkers of Hepatocellular Carcinoma.

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.

• Authors: Jessica Zucman-Rossi, Augusto Villanueva, Jean-Charles Nault, Josep M Llovet
• Journal: Gastroenterology (Gastroenterology) Vol. 149 Issue 5 Pg. 1226-1239.e4 (Oct 2015) ISSN: 1528-0012 [Electronic] United States
• PMID: 26099527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Cyclin-Dependent Kinase Inhibitor p16
• FGF19 protein, human
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Fibroblast Growth Factors
• TERT protein, human
• Telomerase

Topics

• Biomarkers (metabolism)
• Carcinoma, Hepatocellular (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p16 (genetics)
• DNA Copy Number Variations
• Fibroblast Growth Factors (genetics)
• Gene Amplification
• Genetic Predisposition to Disease
• Genomics (methods)
• Hepatitis B (genetics)
• Humans
• Mutation
• Prognosis
• Promoter Regions, Genetic
• Telomerase (genetics)
• Vascular Endothelial Growth Factor A (genetics)