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Cited by 719Hepatocellular Carcinoma Treatment and PrognosisCancer Genomics and DiagnosticsGenomic variations and chromosomal abnormalities

Focal Gains of VEGFA and Molecular Classification of Hepatocellular Carcinoma

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Chiang, Derek Y., Villanueva, Augusto, Hoshida, Yujin, Peix, Judit, Newell, Philippa, Minguez, Beatriz, LeBlanc, Amanda C., Donovan, Diana J. +17 more·2008·Cancer Research
DOI 10.1158/0008-5472.can-08-0742PMC PMC2587454

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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. [Cancer Res 2008;68(16):6779–88]

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  • The CTNNB1-class strongly overlapped with Bouyault's Wnt-related G5-6 classes, which were also characterized by mutations in CTNNB1 and significant over-expression of liver-related Wnt-target-genes.

    “This subclass strongly overlapped with Bouyault’s Wnt-related G5-6 classes, which were also characterized by mutations in CTNNB1 and significant over-expression of liver-related Wnt-target-genes (5, 6).”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [6]

    The Results section (page not available) reports that the CTNNB1-associated class was enriched for CTNNB1 mutations and significantly overexpressed liver-specific marker genes. It also reports strong concordance between two of its classes and external classifiers, but our copy does not identify those predictions as Bouyault’s G5–G6 classes or establish a strong overlap specifically with them. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Our group recently reported two fundamentally different molecular classes associated to Wnt-signaling in HCC based on expression of liver-related (CTNNB1-class) or classical (Wnt-TGFβ-class) Wnt-target-genes.

    “Our group recently reported two fundamentally different molecular classes associated to Wnt-signaling in HCC based on expression of liver-related (CTNNB1-class) or classical (Wnt-TGFβ-class) Wnt-target-genes (6, 8).”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [6]

    The Results section (page not provided) identifies a CTNNB1-associated HCC class with canonical Wnt-signaling alterations and overexpression of liver-specific marker genes. It does not report a second Wnt–TGFβ class defined by classical Wnt-target genes; the other classes it describes include proliferation and interferon-related classes. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The authors previously reported a molecular classification of HCC including a CTNNB1-class characterized by over-expression of liver-related Wnt-target-genes, enrichment in nuclear β-catenin staining and CTNNB1-mutations.

    “We recently reported a molecular classification of HCC, which includes a CTNNB1-class characterized by over-expression of liver-related Wnt-target-genes”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [6]

  • Wnt-signaling associated molecular classes have been reported by different investigators, emphasizing the importance of Wnt-aberrations in liver cancer.

    “Nonetheless, Wnt-signaling associated molecular classes have been reported by different investigators emphasizing the importance of Wnt-aberrations in liver cancer (5, 6).”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [6]

  • No detailed characterization of underlying mechanisms of Wnt-signaling molecular classes in HCC has been pursued yet.

    “Although several molecular classes have been associated with Wnt-signaling in HCC (5, 6, 8) and the concept of liver-related and classical Wnt-signaling has been proposed (29), no detailed characterization of underlying mechanisms has been pursued yet.”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [6]

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Authors
Chiang, D. Y., Villanueva, A., Hoshida, Y., Peix, J., Newell, P., Minguez, B., LeBlanc, A. C., Donovan, D. J., Thung, S. N., Solé, M., Tovar, V., Alsinet, C., Ramos, A. H., Barretina, J., Roayaie, S., Schwartz, M., Waxman, S., Bruix, J., Mazzaferro, V., Ligon, A. H., Najfeld, V., Friedman, S. L., Sellers, W. R., Meyerson, M., & Llovet, J. M.
Affiliations
  • Broad Institute (US)
  • 6Mount Sinai Liver Cancer Program, Division of Liver Diseases,
  • 7Division of Hematology/Oncology, Department of Medicine,
  • Brigham and Women's Hospital (US)
  • 8Department of Pathology, and
  • 10Liver Unit, BCLC Group, HCC Translational Research Lab and Department of Pathology, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain; and
  • Hospital Clínic de Barcelona (ES)
  • Icahn School of Medicine at Mount Sinai (US)
  • 11Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy
  • 5Novartis Institutes for Biomedical Research, Cambridge, Massachusetts;
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2008-08-12
Volume
68
Issue
16
Pages
6779-6788
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-08-0742
PMC
PMC2587454
OpenAlex
W2036922484
Cited by
719
References
6
Citations by year
2026: 18 · 2025: 41 · 2024: 49 · 2023: 65 · 2022: 56 · 2021: 49 · 2020: 49 · 2019: 42 · 2018: 22 · 2017: 37 · 2016: 39 · 2015: 44 · 2014: 45 · 2013: 30 · 2012: 35
FWCI
24.09
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (R01CA109038, CA109038)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK076986, DK037340, DK076986, R01DK037340)
Topics
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
hepatocellular carcinoma, VEGF-A, hepatitis C virus, hepatocarcinogenesis, CTNNB1 mutation, gene expression classification, chromosome 7 polysomy, IGF-1 receptor, S6 phosphorylation, anti-angiogenic therapy, lung adenocarcinoma
MeSH terms
Adenocarcinoma, Chromosome Aberrations, Chromosomes, Human, Pair 6, Chromosomes, Human, Pair 7, Carcinoma, Hepatocellular, Humans, Immunoenzyme Techniques, Karyotyping, Liver Neoplasms, Lung Neoplasms, Neoplasm Staging, Nucleic Acid Hybridization, Prognosis, Biomarkers, Tumor, Signal Transduction, Survival Rate, In Situ Hybridization, Fluorescence, Gene Dosage, Hepatitis B, Chronic, Hepatitis C, Chronic, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Vascular Endothelial Growth Factor A, Tissue Array Analysis

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