Focal gains of VEGFA and molecular classification of hepatocellular carcinoma

Cancer Res. 68(16):6779-88. Published: 2008.08.14

Derek Y. Chiang, Augusto Villanueva, Yujin Hoshida, Judit Peix, Philippa Newell, Beatriz Minguez, Amanda LeBlanc, Diana Donovan, Swan Thung, Manel Sole, Victoria Tovar, Clara Alsinet, Alex Ramos, Jordi Barretina, Sasan Roayaie, Myron Schwartz, Samuel Waxman, Jordi Bruix, Vincenzo Mazzaferro, Azra Ligon, Vesna Najfeld, Scott Friedman, William Sellers, Matthew Meyerson, Josep Llovet

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Abstract

Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. The vast majority of cases arise in the context of chronic liver injury due to hepatitis B virus or hepatitis C virus infection. To identify genetic mechanisms of hepatocarcinogenesis, we characterized copy number alterations and gene expression profiles from the same set of tumors associated with hepatitis C virus. Most tumors harbored 1q gain, 8q gain, or 8p loss, with occasional alterations in 13 additional chromosome arms. In addition to amplifications at 11q13 in 6 of 103 tumors, 4 tumors harbored focal gains at 6p21 incorporating vascular endothelial growth factor A (VEGFA). Fluorescence in situ hybridization on an independent validation set of 210 tumors found 6p21 high-level gains in 14 tumors, as well as 2 tumors with 6p21 amplifications. Strikingly, this locus overlapped with copy gains in 4 of 371 lung adenocarcinomas. Overexpression of VEGFA via 6p21 gain in hepatocellular carcinomas suggested a novel, non-cell-autonomous mechanism of oncogene activation. Hierarchical clustering of gene expression among 91 of these tumors identified five classes, including "CTNNB1", "proliferation", "IFN-related", a novel class defined by polysomy of chromosome 7, and an unannotated class. These class labels were further supported by molecular data; mutations in CTNNB1 were enriched in the "CTNNB1" class, whereas insulin-like growth factor I receptor and RPS6 phosphorylation were enriched in the "proliferation" class. The enrichment of signaling pathway alterations in gene expression classes provides insights on hepatocellular carcinoma pathogenesis. Furthermore, the prevalence of VEGFA high-level gains in multiple tumor types suggests indications for clinical trials of antiangiogenic therapies.

Keywords: VEGFA angiogenesis copy number alterations gene expression hepatocellular carcinoma molecular classification

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Supplemental Data

Description Link/Filename
Copy number alterations: Affymetrix 238K Sty arrays http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE9845
Gene expression: Affymetrix U133 Plus 2 arrays http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE9843