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Focal Gains of VEGFA and Molecular Classification of Hepatocellular Carcinoma

¹ Department of Medical Oncology and Center for Cancer Genome Discovery and ² Department of Pediatric Oncology, Dana-Farber Cancer Institute, ³ Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; ⁴ Cancer Program, Broad Institute of Harvard and MIT, ⁵ Novartis Institutes for Biomedical Research, Cambridge, Massachusetts; ⁶ Mount Sinai Liver Cancer Program, Division of Liver Diseases, ⁷ Division of Hematology/Oncology, Department of Medicine, ⁸ Department of Pathology, and ⁹ Division of Surgical Oncology, Department of Surgery, Mount Sinai School of Medicine, New York, New York; ¹⁰ Liver Unit, BCLC Group, HCC Translational Research Lab and Department of Pathology, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain; and ¹¹ Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy

Requests for reprints: Josep M. Llovet, Division of Liver Diseases, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1123, New York, NY 10029. Phone: 212-659-9503; Fax: 212-849-2574; E-mail: Josep.Llovet{at}mssm.edu or Matthew Meyerson, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Dana 1537, Boston, MA 02115. E-mail: Matthew_Meyerson{at}dfci.harvard.edu.

Key Words: Hepatocellular carcinoma • VEGFA • molecular classification

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. [Cancer Res 2008;68(16):6779–88]

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