Focal Gains of Vascular Endothelial Growth Factor A and Molecular Classification of Hepatocellular Carcinoma

By Derek Y. Chiang, A. Villanueva, Yujin Hoshida, J. Peix, P. Newell, B. Mínguez, A. Leblanc, D. J. Donovan, S. Thung, M. Solé and 15 more. Cancer Research, 2008

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Hepatocellular carcinomas (HCC) 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. In order 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 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, cell-nonautonomous mechanism of oncogene activation. Hierarchical clustering of gene expression among 91 of these tumors identified 5 classes, including ‘CTNNB1’, ‘proliferation’, ‘interferon-related’, and a novel class defined by polysomy of chromosome 7. These class labels were further supported by molecular data: mutations in CTNNB1 were enriched in the ‘CTNNB1’ class, while IGF1R and RPS6 phosphorylation were enriched in the ‘proliferation’ class. The enrichment of signaling pathway alterations in gene expression classes provides insights on HCC pathogenesis. Furthermore, the prevalence of VEGFA high-level gains in multiple tumor types suggests indications for clinical trials of anti-angiogenic therapies.

Subfields: Hepatology, Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/7526d18e3c1cd5c935885eaac00de533930f7d34

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Citations in the corpus

Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification (2020, background): “The prognostic significance of this classification was not determined (Chiang et al., 2008).”
GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers (2011, methodology): “GISTIC has been applied to multiple cancer types, including glioblastoma [10,15], lung adenocarcinoma [16], melanoma [17], colorectal carcinoma [18], hepatocellular carcinoma [19], ovarian carcinoma [20], medulloblastoma [21], and lung and esophageal squamous carcinoma [22], and has helped identify ”
Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. (2014, background): “indicate common genomic traits between iCCA and HCC, supporting the hypothesis of common cell ancestors in specific molecular subclasses: (1) Transcriptome analysis suggests that the poor prognostic subclass of iCCA shares genomic traits and signatures of poor prognosis of HCC [58,60,61], which are ”
Tumor-Associated Macrophages Produce Interleukin 6 and Signal via STAT3 to Promote Expansion of Human Hepatocellular Carcinoma Stem Cells (2014, methodology): “05) using a microarray database.(20) Spearman rank order correlation co-efficient (R) and P value (P) were determined.”
EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. (2012, background): “Around one third of HCCs have activation of the Wnt signaling pathway (particularly HCVrelated HCCs), as a result of activating mutations in the transcription factor ß-catenin [175,317,318], overexpression of Frizzled receptors or inactivation of E-cadherin or members of the degradation complex (GSK”
EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. (2012, background): “Around one third of HCCs have activation of the Wnt signaling pathway (particularly HCVrelated HCCs), as a result of activating mutations in the transcription factor ß-catenin [175,317,318], overexpression of Frizzled receptors or inactivation of E-cadherin or members of the degradation complex (GSK”