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Cited by 1,238Hepatocellular Carcinoma Treatment and PrognosisGene expression and cancer classificationWnt/β-catenin signaling in development and cancer

Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma

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Hoshida, Yujin, Nijman, Sebastian M.B., Kobayashi, Masahiro, Chan, Jennifer A., Brunet, Jean-Philippe, Chiang, Derek Y., Villanueva, Augusto, Newell, Philippa +8 more·2009·Cancer Research
DOI 10.1158/0008-5472.can-09-1089PMC PMC3549578

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Abstract

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomic-based classification for HCC have yielded highly divergent results, indicating difficulty in identifying unified molecular anatomy. We performed a meta-analysis of gene expression profiles in data sets from eight independent patient cohorts across the world. In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort. A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries. We observed three robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum α-fetoprotein levels. An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation. Functional studies indicated that the WNT pathway activation signature characteristic of S1 tumors was not simply the result of β-catenin mutation but rather was the result of transforming growth factor-β activation, thus representing a new mechanism of WNT pathway activation in HCC. These experiments establish the first consensus classification framework for HCC based on gene expression profiles and highlight the power of integrating multiple data sets to define a robust molecular taxonomy of the disease. [Cancer Res 2009;69(18):7385–92]

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  • 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 [8]

    The Results sections “Mechanisms of WNT activation in S1 tumors” and “TGF-beta-WNT interactions” explicitly investigate how WNT signaling is activated, including experiments on TGF-beta stimulation and beta-catenin localization. The Discussion says additional mechanistic studies are required, but that does not support the claim that no characterization had been pursued. (LLM, conf=0.88)

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  • 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 [8]

    In Results (‘Mechanisms of WNT activation in S1 tumors’; page unavailable), the paper distinguishes the S1 WNT signature, characterized by canonical targets such as cyclin D1 and MYC, from the previously reported CTNNB1 class, a subset of S3. It also finds WNT–TGFβ activity in S1. Our copy does not establish that the CTNNB1 class is defined by expression of liver-related WNT target genes, and the paper reports three overall HCC subclasses rather than two. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The importance of Wnt-signaling for the Wnt-TGFβ-class has been proven experimentally.

    “Although the importance of Wnt-signaling for the Wnt-TGFβ-class has been proven experimentally (8), it remains unclear why pathway activation at the protein level is not detected in our set of samples.”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [8]

    In Results > WNT pathway activation in S1, beta-catenin knockdown inhibited growth in a cell line predicted to be S1, which the authors say further supports the hypothesis that WNT activation is functionally important in S1 tumors. The citing sentence overstates this as experimental proof for the class as a whole; the Discussion says additional mechanistic studies are required. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The authors characterized the molecular subclass S1 (Wnt-TGFβ) related to TGFβ-activated Wnt-signaling through a meta-analysis of 603 HCC patients.

    “In parallel, we characterized the molecular subclass S1 (Wnt-TGFβ) related to TGFβ-activated Wnt-signaling through a meta-analysis of 603 HCC patients (8).”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [8]

  • Wnt-TGFβ-class was associated with TGF-β activation, cytoplasmic β-catenin staining, vascular invasion, satellitosis and greater risk of early recurrence after surgical resection.

    “While the CTNNB1-class was correlated with CTNNB1-mutations, nuclear β-catenin staining and tumor diameter >3cm (6), Wnt-TGFβ-class was associated with TGF-β activation, cytoplasmic β-catenin staining, vascular invasion, satellitosis and greater risk of early recurrence after surgical resection (8).”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [8]

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Research works printed but not linked: 37

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Authors
Hoshida, Y., Nijman, S. M. B., Kobayashi, M., Chan, J. A., Brunet, J.-P., Chiang, D. Y., Villanueva, A., Newell, P., Ikeda, K., Hashimoto, M., Watanabe, G., Gabriel, S., Friedman, S. L., Kumada, H., Llovet, J. M., & Golub, T. R.
Affiliations
  • Broad Institute (US)
  • Toranomon Hospital (JP)
  • Hospital Clínic de Barcelona (ES)
  • Icahn School of Medicine at Mount Sinai (US)
  • Institució Catalana de Recerca i Estudis Avançats (ES)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2009-09-14
Volume
69
Issue
18
Pages
7385-7392
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-09-1089
PMC
PMC3549578
OpenAlex
W2136415416
Cited by
1,238
References
1
Citations by year
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FWCI
23.56
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • RIKEN
  • National Cancer Institute (U54CA112962)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK076986)
Topics
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
hepatocellular carcinoma, molecular subtypes, gene expression profiling, Wnt signaling, TGF-beta, β-catenin, MYC activation, Akt activation, hepatocyte differentiation, alpha-fetoprotein, hepatitis B, hepatitis C, tumor heterogeneity, consensus classification
MeSH terms
Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Cohort Studies, Signal Transduction, Transforming Growth Factor beta, Gene Expression Profiling, Cell Line, Tumor, Wnt Proteins, beta Catenin

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