Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets
Open accessAbstract
Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. We further investigated transcriptome-genotype-phenotype correlations in HCC. Global transcriptome analyses were performed on 57 HCCs and 3 hepatocellular adenomas and validated by quantitative RT-PCR using 63 additional HCCs. We determined loss of heterozygosity, gene mutations, promoter methylation of CDH1 and CDKN2A , and HBV DNA copy number for each tumor. Unsupervised transcriptome analysis identified 6 robust subgroups of HCC (G1-G6) associated with clinical and genetic characteristics. G1 tumors were associated with low copy number of HBV and overexpression of genes expressed in fetal liver and controlled by parental imprinting. G2 included HCCs infected with a high copy number of HBV and mutations in PIK3CA and TP53 . In these first groups, we detected specific activation of the AKT pathway. G3 tumors were typified by mutation of TP53 and overexpression of genes controlling the cell cycle. G4 was a heterogeneous subgroup of tumors including TCF1 -mutated hepatocellular adenomas and carcinomas. G5 and G6 were strongly related to β-catenin mutations that lead to Wnt pathway activation; in particular, G6 tumors were characterized by satellite nodules, higher activation of the Wnt pathway, and E-cadherin underexpression. Conclusion: These results have furthered our understanding of the genetic diversity of human HCC and have provided specific identifiers for classifying tumors. In addition, our classification has potential therapeutic implications because 50% of the tumors were related to WNT or AKT pathway activation, which potentially could be targeted by specific inhibiting therapies. (Hepatology 2007;45:42–52.rpar;
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Aberrant activation of Wnt can result from mutations in CTNNB1, which is the second most frequent mutation observed in HCC after TP53.
“Aberrant activation of Wnt can also result from mutations in the β-catenin gene (CTNNB1), which is the second most frequent mutation observed in HCC after the p53 tumor suppressor (TP53) (5).”
From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [5]
The paper’s introductory discussion of HCC pathways says Wnt activation occurs mainly through CTNNB1 mutations, and the Results identify CTNNB1 and TP53 as frequent somatic mutations. Neither passage establishes that CTNNB1 is the second most frequent mutation in HCC after TP53. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe CTNNB1-mutation-signature was validated in one dataset where CTNNB1 mutations were reported.
“Specifically, CTNNB1-mutation-signature was validated in one dataset where CTNNB1 mutations were reported (5).”
From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [5]
The Results section says the association between the G5–G6 transcriptomic groups and CTNNB1 mutations was validated in a second, independent set of 63 tumors. The 'Identification of a predictor' section describes the signature as a 16-gene predictor of six HCC groups, however, not a CTNNB1-mutation-specific signature. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe CTNNB1-mutation signature's prediction accuracy was 91% when tested in an independent dataset.
“Its prediction accuracy was 91% when tested in an independent dataset (5) and it was enriched in CTNNB1-class in 6 independent HCC datasets, underscoring the idea that CTNNB1-Wnt is activated and driven by CTNNB1- mutations in HCC.”
From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [5]
The ‘Identification of a predictor of the 6-groups classification’ section (page unavailable) says a 16-gene signature classified 45 of 46 previously characterized HCCs and was then used to partition 63 independent tumors. The Results associate two of those groups with CTNNB1 mutations, but the paper does not report 91% prediction accuracy for a CTNNB1-mutation signature in the independent set. (LLM, conf=0.86)
Experimental — accuracy not yet measuredWnt-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 [5]
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 [5]
The ability of the CTNNB1-mutation signature to capture CTNNB1 mutated samples was validated in one HCC dataset.
“The ability of the signature to capture CTNNB1 mutated samples was validated in one HCC dataset (5).”
From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [5]
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 [5]
Common Wnt pathway target genes MYC and CCND1 were not found to be associated to Wnt activation in the liver.
“Interestingly, common Wnt pathway target genes MYC and CCND1 were not found to be associated to Wnt activation in the liver, as described elsewhere (5, 31).”
From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [5]
The Wnt-activation section identifies other β-catenin target genes in liver tumors but does not say whether MYC or CCND1 is associated with Wnt activation. Searches for MYC, CCND1, and cyclin D1 found no passage addressing that specific claim. (LLM, conf=0.73)
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- Authors
- Boyault, S., Rickman, D. S., de Reyniès, A., Balabaud, C., Rebouissou, S., Jeannot, E., Hérault, A., Saric, J., Belghiti, J., Franco, D., Bioulac-Sage, P., Laurent-Puig, P., & Zucman-Rossi, J.
- Affiliations
- Inserm (FR)
- La Ligue Contre le Cancer (FR)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- Hôpital Beaujon (FR)
- ORCID
- Venue
- Hepatology
- Published
- 2007-01
- Volume
- 45
- Issue
- 1
- Pages
- 42-52
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2023815439
- Cited by
- 1,258
- References
- 0
- Citations by year
- 2026: 29 · 2025: 57 · 2024: 93 · 2023: 86 · 2022: 93 · 2021: 112 · 2020: 77 · 2019: 68 · 2018: 49 · 2017: 58 · 2016: 55 · 2015: 68 · 2014: 67 · 2013: 61 · 2012: 68
- FWCI
- 21.10
- Type
- journal article
- Language
- en
- Open access
- green
- inserm.hal.science
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Association pour la Recherche sur le Cancer
- Fondation de France
- 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 › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- hepatocellular carcinoma, tumor subtypes, hepatocellular adenoma, loss of heterozygosity, PIK3CA mutation, TP53 mutation, CTNNB1 mutation, satellite nodules, E-cadherin, therapeutic target, tumor heterogeneity
- MeSH terms
- Adenoma, DNA, Neoplasm, Female, Multigene Family, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Middle Aged, Mutation, Transcription, Genetic, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Nuclear Pore Complex Proteins, Proto-Oncogene Proteins c-akt, Wnt Proteins, Genes, Neoplasm, Class I Phosphatidylinositol 3-Kinases
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