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Convergent somatic mutations in metabolism genes in chronic liver disease
Open accessAbstract
The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20-30 cancer genes 1-8. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease 9-13 than in normal liver 13-16, which enables positive selection to shape the genomic landscape 9-13. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease. Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1. Notably, six of the seven patients with FOXO1 S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes 17-19, and GPAM, which produces storage triacylglycerol from free fatty acids 20,21, also had a significant excess of mutations. We again observed frequent convergent evolution: up to fourteen independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both alcohol-related liver disease and non-alcoholic fatty liver disease, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and non-alcoholic fatty liver disease.
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“In NASH livers, Ng et. al. identified convergent mutations in genes central to insulin signaling and lipogenesis6.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [6]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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 [9]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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 [9]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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 [9]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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 [9]
Experimental — accuracy not yet measured
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In the citing paper
“Somatic mutations are common in nonmalignant liver tissues, but mutations in cancer drivers are observed less frequently than anticipated (7–9).”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [9]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“These loss of function mutations in metabolic enzymes that generate hepatic lipids suggest that some somatic mutations can confer increased fitness through a reversal of the driving etiology of disease.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [6]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“This concept was strengthened by the fact that the same mutated genes such as Gpam and Acvr2a were selected for in both mouse and human tissues6.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [6]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Interestingly, Acvr2a and Gpam are two of the most recurrently mutated genes in cirrhotic tissues from alcoholic liver disease and NASH patients6.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [6]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Mutant clone expansion and recurrent mutations within and between individuals provide compelling evidence for increased mutant clone fitness in chronic liver disease6.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [6]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“A consistent pattern has been observed across most, if not all, tissues: after an initial expansion of the stem cell pool during early life, clonal heterogeneity tends to diminish over time (Figure 1).17-24”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [24]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Interestingly, these selected and more fit clones may share genomic events such as nonsynonymous mutations initially thought to be restricted to cancer.17-24”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [24]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Examples include the possible links between clonal haematopoiesis and cardiovascular disease54; between mutations in liver disease and insulin resistance55; and between driver mutations in cavernomas and brain haemorrhages49,53,56.”
From Somatic mutation rates scale with lifespan across mammals (2022) · cites this paper as [55]
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“For example, liver samples from human patients with fatty liver disease frequently have mutations in FOXO1, CIDEB and GPAM, three master regulators of lipid processing and storage, but similar mutations are not significantly enriched in hepatocellular carcinomas from human patients [37].”
BackgroundEffects of psoriasis and psoralen exposure on the somatic mutation landscape of the skin
Ólafsson, S., Rodríguez, E., Lawson, A. R. J., Abascal, F., Huber, A. R., Suembuel, M., Jones, P. H., Gerdes, S., Martincorena, I., Weidinger, S., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01545-1 · Cited by 23
“We performed Bayesian clustering of mutations based on their VAFs in different microbiopsies and used the statistical pigeonhole principle to derive a phylogenetic relationship between the clusters 8,9 (Fig.”
BackgroundMethodSelf-citationOgasawara, T., Fujii, Y. R., Kakiuchi, N., Shiozawa, Y., Sakamoto, R., Ogawa, Y., Ootani, K., Ito, E., Tanaka, T., Watanabe, K., et al. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac362 · Cited by 21
FoxO3 restricts liver regeneration by suppressing the proliferation of hepatocytes
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“This approach has recently been applied to construct phylogenies of polyclonal samples of normal tissues, such as the liver 41,46 .”
Self-citationClonal Hematopoiesis: Connecting Aging and Inflammation in Atherosclerosis
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Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer
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Tissue mosaicism following stem cell aging: blood as an exemplar
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“External exacerbations of underlying mosaicism occur in other tissues as well, for example, in the colon of patients with inflammatory bowel disease 126 and in the liver of patients with chronic liver disease 127 , both underlaid by inflammatory tissues.”
Zanotti, S., Boot, G. F., Coto‐Llerena, M., Gallon, J., Hess, G. F., Soysal, S. D., Kollmar, O., Ng, C. K. Y., & Piscuoglio, S. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.888850 · Cited by 17
“Of note, mutations in metabolism genes were observed in both ALD and NAFLD but less frequently in HCC (28).”
BackgroundUnveiling the cancer risk nexus of the steatotic liver
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Somatic Mutations in Normal Tissues: New Perspectives on Early Carcinogenesis
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Aberrant basal cell clonal dynamics shape early lung carcinogenesis
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“A nonparametric Bayesian hierarchical Dirichlet process (HDP) was implemented to cluster SNVs with similar variant allele frequencies (VAFs) that were called across multiple microdissections for each patient biopsy as described previously (39).”
InfluentialSelf-citationHe, L., She, X., Guo, L., Gao, M., Wang, S., Lu, Z., Guo, H.-T., Li, R., Nie, Y., Xing, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58790-7 · Cited by 16
“Somatic missense, nonsense, and frameshift mutations of GPAM have been identi fi ed in biopsy specimens of liver from patients with MASLD and alcohol-related liver disease 8 .”
Pilet, J., Hirsch, T. Z., Gupta, B., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42418-9 · Cited by 16
Relationships Between Regeneration, Wound Healing, and Cancer
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Implementing Mutational Epidemiology on a Global Scale: Lessons from Mutographs
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Self-citationSingle-cell genotype-phenotype mapping identifies therapeutic vulnerabilities in VEXAS syndromePreprint
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Emerging and potential use of CRISPR in human liver disease
Adlat, S., Vázquez-Salgado, A. M., Lee, M., Yin, D., & Wangensteen, K. J. (2023) · Hepatology · doi:10.1097/hep.0000000000000578 · Cited by 19
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“Cell Viability ð%Þ 1⁄4 ODsample-ODblank ODcontrol-ODblank 100% (2)”
A genetic hypothesis for burnt‐out steatohepatitis
Valenti, L. V. C., Romeo, S., & Pajvani, U. B. (2021) · Liver International · doi:10.1111/liv.15103 · Cited by 14
The many pathways driving liver inflammation in MASH
Tilg, H., Adolph, T. E., Romeo, S., & Loomba, R. S. (2026) · Cell Metabolism · doi:10.1016/j.cmet.2026.02.018 · Cited by 17
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“39,40 These observations, taken together, suggest that SPNs arise from an independent distinct origin as a result of positive selection of GNAS -mutated clones in adreno-cortical tissues, rather than from a common clone that branched off from a single origin.”
Somatic mutation and selection at epidemiological scalePreprint
Lawson, A., Abascal, F., Nicola, P., Lensing, S., Roberts, A., Kalantzis, G., Baez-Ortega, A., Brzozowska, N., Moustafa, J. E.-S., Vaitkute, D., et al. (2024) · medRxiv · doi:10.1101/2024.10.30.24316422 · Cited by 10
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Self-citationSomatic evolution following cancer treatment in normal tissue
Pich, O., Ward, S., Rowan, A., Naceur‐Lombardelli, C., Shutkever, O., Martínez‐Ruiz, C., Harries, S., Hessey, S., Naidu, B. V., Brenton, J. D., et al. (2025) · Nature · doi:10.1038/s41586-025-09792-4 · Cited by 17
“This signature bears similarity to published signatures described in the context of chronic liver disease 21 and hepatocellular carcinomas 22,23 (Extended Data Fig.”
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“In this study, we explored somatic variants and clonal dynamics in the liver of patients with end-stage CLD caused by hemochromatosis and A1AT deficiency.”
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Steatotic liver disease induces YAP/TAZ-driven cell competition that can suppress tumor initiation
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Epigenetic memory of environmental exposures as a mediator of liver disease
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PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer
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“Additionally, recent theories suggest that, as an adaptation to prolonged lipotoxicity in hepatocytes in fatty liver disease, clonal selection occurs for cells with somatic mutagenesis in genes related to insulin and lipid synthesis signaling, leading to reduced fat accumulation [32, 33].”
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“Liver dysfunction develops through the combined influence of several factors, including metabolic overload, activation of innate immune responses, exposure to xenobiotics, and drug-induced injury [1–5].”
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“These responses contribute to premalignant events, including oxidant-induced DNA damage and mutations in metabolic genes such as FOXO1 , CIDEB , and GPAM [74, 75].”
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Evolution of Multiple Myeloma from a Genomic Perspective
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Genetic screening of liver cancer: State of the art
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Metadata
- Authors
- Ng, S. W. K., Rouhani, F. J., Brunner, S. F., Brzozowska, N., Aitken, S. J., Yang, M., Abascal, F., Moore, L., Nikitopoulou, E., Chappell, L., Leongamornlert, D., Ivovic, A., Robinson, P., Butler, T., Sanders, M. A., Williams, N., Coorens, T. H. H., Teague, J., Raine, K., Butler, A. P., Hooks, Y., Wilson, B., Birtchnell, N., Naylor, H., Davies, S. E., Stratton, M. R., Martincorena, I., Rahbari, R., Frezza, C., Hoare, M., & Campbell, P. J.
- Affiliations
- Wellcome Sanger Institute (GB)
- University of Cambridge (GB)
- Erasmus MC (NL)
- Addenbrooke's Hospital (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Corresponding author
- Hoare, Matthew
- Campbell, Peter J.
- ORCID
- Ng, Stanley W. K.
- Rouhani, Foad J.
- Brunner, Simon F.
- Brzozowska, Natalia
- Aitken, Sarah J.
- Yang, Ming
- Abascal, Federico
- Moore, Luiza
- Nikitopoulou, Efterpi
- Chappell, Lia
- Leongamornlert, Daniel
- Ivovic, Aleksandra
- Robinson, Philip
- Butler, Timothy
- Sanders, Mathijs A.
- Williams, Nicholas
- Coorens, Tim H. H.
- Teague, Jon
- Raine, Keiran
- Naylor, Huw
- Davies, Susan E.
- Stratton, Michael R.
- Martincorena, Iñigo
- Rahbari, Raheleh
- Frezza, Christian
- Hoare, Matthew
- Campbell, Peter J.
- Venue
- Nature
- Published
- 2021-10-13
- Volume
- 598
- Issue
- 7881
- Pages
- 473-478
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3206615564
- Cited by
- 190
- References
- 54
- Citations by year
- 2026: 25 · 2025: 45 · 2024: 46 · 2023: 41 · 2022: 31 · 2021: 2
- FWCI
- 12.30
- Type
- journal article
- Language
- en
- Open access
- green
- pure.eur.nl
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- European Hematology Association (TRTH182)
- Wellcome Trust
- Cancer Research UK (26813, 29681, 19924, C14303 / A17197, 21777, 24032, 22310, 27114)
- National Institute for Health and Care Research (CL-2019-14-003, CL-2016-14-004)
- Academy of Medical Sciences (SGL019\1092)
- Medical Research Council (MC_UU_12022/6)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- somatic mutations, convergent evolution, chronic liver disease, hepatocellular carcinoma, FOXO1, CIDEB, GPAM, metabolic genes, alcoholic liver disease, non-alcoholic fatty liver disease, clonal expansion, driver mutations, insulin signaling, lipid droplet metabolism, triglyceride synthesis
- MeSH terms
- Forkhead Box Protein O1, Chronic Disease, Fatty Acids, Nonesterified, Female, Humans, Insulin Resistance, Liver, Liver Diseases, Liver Diseases, Alcoholic, Male, Mutation, Triglycerides, Cohort Studies, Active Transport, Cell Nucleus, Cell Line, Tumor, Apoptosis Regulatory Proteins, Non-alcoholic Fatty Liver Disease
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