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Cited by 250Liver physiology and pathologyCancer Genomics and DiagnosticsLiver Disease Diagnosis and Treatment

Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease

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Zhu, Min, Lu, Tianshi, Jia, Yuemeng, Luo, Xin, Gopal, Purva, Li, Lin, Odewole, Mobolaji, Renteria, Veronica +10 more·2019·Cell
DOI 10.1016/j.cell.2019.03.026PMC PMC6519461
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Abstract

Normal tissues accumulate genetic changes with age, but it is unknown if somatic mutations promote clonal expansion of non-malignant cells in the setting of chronic degenerative diseases. Exome sequencing of diseased liver samples from 82 patients revealed a complex mutational landscape in cirrhosis. Additional ultra-deep sequencing identified recurrent mutations in PKD1, PPARGC1B, KMT2D, and ARID1A. The number and size of mutant clones increased as a function of fibrosis stage and tissue damage. To interrogate the functional impact of mutated genes, a pooled in vivo CRISPR screening approach was established. In agreement with sequencing results, examination of 147 genes again revealed that loss of Pkd1, Kmt2d, and Arid1a promoted clonal expansion. Conditional heterozygous deletion of these genes in mice was also hepatoprotective in injury assays. Pre-malignant somatic alterations are often viewed through the lens of cancer, but we show that mutations can promote regeneration, likely independent of carcinogenesis.

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  • Some mutations found in cirrhotic livers induce liver regeneration without promoting cancer.

    “Importantly, some of these mutations induce liver regeneration without promoting cancer (31, 32).”

    From Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion (2025) · cites this paper as [31]

    The Introduction reports that recurrently mutated genes with large effects on liver regeneration are not frequently detected in liver cancer. But it says they ‘do not appear to promote carcinogenesis,’ and the Discussion calls regeneration without transformation ‘likely’; the claim presents that uncertain conclusion as established. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • After decades of injury, cirrhotic livers consist of millions of nodules, most of which harbor somatic mutations.

    “After decades of injury, cirrhotic livers consist of millions of nodules, most of which harbor somatic mutations (7–9).”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [7]

    The Introduction (page not available) identifies regenerative nodules as a defining feature of cirrhosis, and the Discussion says decades of liver damage can lead to cirrhosis and that mutations in cirrhosis are common. The paper does not state that a cirrhotic liver contains millions of nodules or establish that most nodules harbor somatic mutations; the Results say the authors could not assign mutations to individual nodules. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • TP53 and CTNNB1 mutations do not drive extensive clonal expansion events before tumor initiation.

    “The HCC driver genes TP53 (tumor protein p53) and CTNNB1 (catenin beta 1) are not the most frequently observed mutant genes in the cirrhotic liver (7–9), suggesting that these mutations do not drive extensive clonal expansion events before tumor initiation.”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [7]

    The Results (Ultra-deep targeted sequencing identified recurrent somatic mutations; page unavailable) report TRP53 mutations in 6% of patients and say CTNNB1 was not detected in more than two patients, suggesting different selection pressures in HCC and background liver. These findings support the citing sentence’s observation about mutation frequency, but the paper does not establish that TP53 and CTNNB1 mutations do not drive extensive clonal expansion before tumor initiation. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The inefficient CreER recombination faithfully modeled the somatic mosaicism seen in human livers before cancer development.

    “While this showed that CreER was not 100% efficient, it also faithfully modeled the somatic mosaicism seen in human livers before cancer development (7–9, 33).”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [7]

    The Introduction reports somatic mutations and evidence of clonal expansion in non-dysplastic human liver tissue, supporting the claim that mosaicism exists before cancer. The paper does not assess inefficient CreER recombination or establish that it faithfully models that mosaicism; its mouse methods describe other approaches. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Somatic mutations are common in most individuals, and mutation burden increases with age and chronic tissue damage.

    “Somatic mutations are common in most individuals, and there is accumulating evidence that mutation burden increases with age and chronic tissue damage1-4.”

    From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [3]

    The Introduction (page unavailable) says aging is associated with extensive somatic mutagenesis across multiple tissues. The Results and Discussion (page unavailable) report that mutation counts increase with fibrosis and damage in diseased liver. The copy does not establish that somatic mutations are common in most individuals or that chronic damage increases mutation burden across tissues generally; in this liver cohort, mutation count was not associated with age. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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References 67 · Cited by 250

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Authors
Zhu, M., Lu, T., Jia, Y., Luo, X., Gopal, P., Li, L., Odewole, M., Renteria, V., Singal, A. G., Jang, Y., Ge, K., Wang, S. C., Sorouri, M., Parekh, J. R., MacConmara, M. P., Yopp, A. C., Wang, T., & Zhu, H.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • National Institutes of Health (US)
  • Harold C. Simmons Comprehensive Cancer Center (US)
Corresponding author
  • Wang, Tao
  • Zhu, Hao
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2019-04
Volume
177
Issue
3
Pages
608-621.e12
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2019.03.026
PMC
PMC6519461
OpenAlex
W2929496863
Cited by
250
References
67
Citations by year
2026: 23 · 2025: 26 · 2024: 29 · 2023: 28 · 2022: 39 · 2021: 49 · 2020: 40 · 2019: 15
FWCI
23.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Burroughs Wellcome Fund
  • Stand Up To Cancer (SU2C-AACR-IRG 10-16)
  • Cancer Prevention and Research Institute of Texas (RP150596)
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK111588, R1209)
  • Entertainment Industry Foundation
  • American Association for Cancer Research
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
somatic mutations, clonal expansion, liver regeneration, chronic liver disease, liver cirrhosis, liver fibrosis, PKD1, PPARGC1B, KMT2D, ARID1A, CRISPR screen, hepatoprotection, heterozygous deletion, degenerative diseases
MeSH terms
Exome Sequencing, Animals, Chronic Disease, DNA-Binding Proteins, Female, Humans, Hydrolases, Liver, Liver Cirrhosis, Liver Diseases, Male, Middle Aged, Mutation, Neoplasm Proteins, Nuclear Proteins, Regeneration, Transcription Factors, RNA-Binding Proteins, Mice, Knockout, TRPP Cation Channels, Mice, Clustered Regularly Interspaced Short Palindromic Repeats

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