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Cited by 424Hepatocellular Carcinoma Treatment and PrognosisCancer Genomics and DiagnosticsHepatitis B Virus Studies

Genomic portrait of resectable hepatocellular carcinomas: Implications of RB1 and FGF19 aberrations for patient stratification

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Ahn, Sung‐Min, Jang, Se Jin, Shim, Ju Hyun, Kim, Deokhoon, Hong, Seung‐Mo, Sung, Chang Ohk, Baek, Daehyun, Haq, Farhan +21 more·2014·Hepatology
DOI 10.1002/hep.27198
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Abstract

UNLABELLED: Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (multivariate P = 0.038 and P = 0.012, respectively). FGF19 amplifications, known to activate Wnt signaling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (P = 0.017). CONCLUSION: RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients.

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  • In patients with HCC, high PROX1 expression is associated with increased survival.

    “in patients with HCC, high PROX1 expression or chromosomal amplifications including PROX1 were both associated with increased survival25–32”

    From Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis (2025) · cites this paper as [25]

    The Clinical Features section discusses amplifications involving FGF19 and other genes, while the survival analysis in Genetic Aberrations in HCC concerns RB1 mutations. Searches for PROX1 expression and PROX1-containing amplifications found no passage linking PROX1 to survival. Page numbers were not available in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • In patients with HCC, chromosomal amplifications including PROX1 are associated with increased survival.

    “in patients with HCC, high PROX1 expression or chromosomal amplifications including PROX1 were both associated with increased survival25–32”

    From Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis (2025) · cites this paper as [25]

    The Clinical Features section lists recurrent chromosomal amplifications in HCC, but does not identify PROX1 among them. The postsurgical-outcomes section links RB1 mutations—not PROX1 amplification—to survival. A search for PROX1 found no passage supporting the claimed association with increased survival; page numbers were unavailable in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • TBX3 expression is negatively correlated with TP53 mutations in human HCCs.

    “TBX3 expression was found to be negatively correlated with TP53 mutations (Fig. 1B and Fig. S1A, C).”

    From TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis (2021) · cites this paper as [15]

    The Clinical Features section reports TP53 mutation rates and associations with tumor grade and other genetic alterations, but not with TBX3 expression. Searches for “TBX3 expression TP53 mutations” and “TBX3” found no passage addressing the claimed negative correlation; page numbers were not available in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cites

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Cited by

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Authors
Ahn, S., Jang, S. J., Shim, J. H., Kim, D., Hong, S., Sung, C. O., Baek, D., Haq, F., Ansari, A. A., Lee, S. Y., Chun, S., Choi, S., Choi, H., Kim, J., Kim, S., Hwang, S., Lee, Y., Lee, J., Jung, W., Jang, H. Y., Yang, E., Sung, W., Lee, N. P., Mao, M., Lee, C., Zucman‐Rossi, J., Yu, E., Lee, H. C., & Kong, G.
Affiliations
  • Asan Medical Center (KR)
  • Seoul National University (KR)
  • Gachon University (KR)
  • DNA Link, Inc. Seoul Korea
  • JS Link (South Korea) (KR)
  • National University of Singapore (SG)
  • Department of SurgeryUniversity of Hong King Hong King China
  • WuXi AppTec (China) (CN)
  • The Jackson Laboratory for Genomic Medicine (US)
  • Inserm (FR)
  • Hanyang University (KR)
Corresponding author
  • Yu, Eunsil
  • Lee, Han Chu
  • Kong, Gu
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2014-09-22
Volume
60
Issue
6
Pages
1972-1982
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.27198
OpenAlex
W2018080595
Cited by
424
References
1
Citations by year
2026: 14 · 2025: 18 · 2024: 35 · 2023: 26 · 2022: 44 · 2021: 56 · 2020: 34 · 2019: 44 · 2018: 41 · 2017: 40 · 2016: 31 · 2015: 34 · 2014: 6
FWCI
20.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders
  • National Research Foundation
  • Ministry of Science, ICT and Future Planning (2011-0030105)
  • National Research Foundation of Korea (2011-0030105)
Topics
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
Keywords
hepatocellular carcinoma, resectable liver cancer, RB1 mutation, tumor recurrence, prognostic factors, patient stratification, TP53, CTNNB1, AXIN1, Wnt signaling, p53 pathway, liver cirrhosis, hepatitis B, CDKN2A, c-Myc, hepatocarcinogenesis
MeSH terms
Adult, Aged, Aged, 80 and over, DNA Mutational Analysis, Female, Fibroblast Growth Factors, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Middle Aged, Biomarkers, Tumor, Retinoblastoma Protein, E2F1 Transcription Factor, DNA Copy Number Variations

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