Data from Focal Gains of <i>VEGFA</i> and Molecular Classification of Hepatocellular Carcinoma

<div>Abstract<p>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 <i>vascular endothelial growth factor A</i> (<i>VEGFA</i>). Fluorescence <i>in situ</i> 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 “<i>CTNNB1</i>”, “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 <i>CTNNB1</i> were enriched in the “<i>CTNNB1</i>” 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 <i>VEGFA</i> high-level gains in multiple tumor types suggests indications for clinical trials of antiangiogenic therapies. [Cancer Res 2008;68(16):6779–88]</p></div>