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Cited by 393Cancer Genomics and DiagnosticsLiver physiology and pathologyHepatitis B Virus Studies

Somatic mutations and clonal dynamics in healthy and cirrhotic human liver

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Brunner, Simon F., Roberts, Nicola D., Wylie, Luke A., Moore, Luiza, Aitken, Sarah J., Davies, Susan E., Sanders, Mathijs A., Ellis, Pete +7 more·2019·Nature
DOI 10.1038/s41586-019-1670-9PMC PMC6837891
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Abstract

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes 1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures 8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.

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  • 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 [8]

    The paper’s Abstract (page unavailable) reports somatic mutations in cirrhotic liver and describes mutated clones within nodules separated by fibrotic bands. It does not establish that cirrhotic livers contain millions of nodules, that most nodules harbor mutations, or a specific duration of decades of injury. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The HCC driver genes TP53 and CTNNB1 are not the most frequently observed mutant genes in the cirrhotic liver.

    “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 [8]

    The driver-mutation analysis (section labelled Abstract; page unavailable) identifies ALB and ACVR2A, rather than TP53 or CTNNB1, as significant among the 30 HCC genes tested. It does not give a gene-frequency ranking specifically for cirrhotic liver; its reported variants combine normal and cirrhotic samples. (LLM, conf=0.78)

    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 [8]

    The concluding passage (labeled Abstract in our copy; page unavailable) says driver mutations in non-malignant liver did not drive large clonal expansions. The driver-screening passage in the same section identifies other genes but does not establish this finding specifically for TP53 or CTNNB1, or show how frequently those two genes were mutated in cirrhotic liver. (LLM, conf=0.83)

    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 [8]

    The paper describes non-malignant human liver as a “clonal patchwork” and healthy liver as a community of small clones (Abstract; page unavailable), supporting the claim that mosaicism exists before liver cancer. It does not examine CreER recombination or establish that inefficient recombination faithfully models that mosaicism. (LLM, conf=0.84)

    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 [2]

    The Abstract reports somatic mutations in normal liver, a higher mutation burden in cirrhotic than normal liver, and a signature that accumulates with age. The study examined liver samples from 14 people, so it does not establish that somatic mutations are common in most individuals generally; its estimated age-related increase in overall mutation burden also had wide confidence intervals and was not statistically significant. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cites

Flagged first, then by citations

Research works printed but not linked: 40

  1. [1]The Cancer Genome Atlas Research Network Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma Cell 2017 169 1327 1341 28622513 PMC5680778
  2. [2]Schulze K Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets Nat Genet 2015 47 505 511 25822088 PMC4587544
  3. [4]Fujimoto A Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators Nat Genet 2012 44 760 4 22634756
  4. [5]Letouzé E Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis Nat Commun 2017 8 PMC5670220 29101368
  5. [6]Kan Z Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma Genome Res 2013 23 1422 1433 23788652 PMC3759719
  6. [7]Guichard C Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma Nat Genet 2012 44 694 8 22561517 PMC3819251
  7. [9]Lodato MA Aging and neurodegeneration are associated with increased mutations in single human neurons Science (80-.) 2017 559 1 8 PMC5831169 29217584
  8. [10]Lee-Six H Population dynamics of normal human blood inferred from somatic mutations Nature 2018 561 473 478 30185910 PMC6163040
  9. [11]Martincorena I High burden and pervasive positive selection of somatic mutations in normal human skin Science (80-.) 2015 348 880 886 PMC4471149 25999502
  10. [12]Fellous TG Locating the stem cell niche and tracing hepatocyte lineages in human liver Hepatology 2009 49 1655 63 19309719
  11. [13]Sigal SH Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events Am J Physiol 1999 276 G1260 72 10330018
  12. [14]Stephens PJ Massive genomic rearrangement acquired in a single catastrophic event during cancer development Cell 2011 144 27 40 21215367 PMC3065307
  13. [15]Fernandez-Banet J Decoding complex patterns of genomic rearrangement in hepatocellular carcinoma Genomics 2014 103 189 203 24462510
  14. [16]Imielinski M Guo G Meyerson M Insertions and Deletions Target Lineage-Defining Genes in Human Cancers Cell 2017 168 460 472.e14 28089356 PMC5564321
  15. [17]Martincorena I Universal Patterns of Selection in Cancer and Somatic Tissues Cell 2017 171 1029 1041 29056346 PMC5720395
  16. [18]Torrecilla S Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma J Hepatol 2017 67 1222 1231 28843658
  17. [21]Osorio FG Somatic Mutations Reveal Lineage Relationships and Age-Related Mutagenesis in Human Hematopoiesis Cell Rep 2018 25 2308 2316.e4 30485801 PMC6289083
  18. [22]Haradhvala NJ Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair Cell 2016 164 538 549 26806129 PMC4753048
  19. [23]Poon SL Genome-wide mutational signatures of aristolochic acid and its application as a screening tool Sci Transl Med 2013 5 197ra101 23926199
  20. [24]Scelo G Variation in genomic landscape of clear cell renal cell carcinoma across Europe Nat Commun 2014 5 5135 25351205
  21. [25]Rushing BR Selim MI Aflatoxin B1: A review on metabolism, toxicity, occurrence in food, occupational exposure, and detoxification methods Food Chem Toxicol 2018 124 81 100 30468841
  22. [26]Martincorena I Somatic mutant clones colonize the human esophagus with age Science (80-.) 2018 917 911 917 PMC6298579 30337457
  23. [28]Nault JC Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis Hepatology 2014 60 1983 92 25123086
  24. [29]Kim SK Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis J Gastroenterol 2019 10.1007/s00535-019-01555-z 30756187 · DOI
  25. [30]Zhu M Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease Cell 2019 1 14 10.1016/j.cell.2019.03.026 PMC6519461 30955891 · DOI · Paper page
  26. [31]Kleiner DE Design and validation of a histological scoring system for nonalcoholic fatty liver disease Hepatology 2005 41 1313 1321 15915461
  27. [32]Lee-Six H The landscape of somatic mutation in normal colorectal epithelial cells bioRxiv 2018 10.1101/416800 416800 31645730 · DOI
  28. [33]Jones D cgpCaVEManWrapper: Simple Execution of CaVEMan in Order to Detect Somatic Single Nucleotide Variants in NGS Data Current Protocols in Bioinformatics John Wiley & Sons, Inc 2016 15.10.1 15.10.18 2016 PMC6097605 27930805
  29. [34]Menzies A VAGrENT: Variation Annotation Generator Curr Protoc Bioinformatics 2015 52 15.8.1 15.8.11 PMC6101192 26678383
  30. [37]Fujimoto A Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity Nat Commun 2015 6 1 8 25636086
  31. [38]Cleary SP Identification of driver genes in hepatocellular carcinoma by exome sequencing Hepatology 2013 58 1693 702 23728943 PMC3830584
  32. [39]Ahn S-M Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification Hepatology 2014 60 1972 82 24798001
  33. [40]Raine KM cgpPindel: Identifying Somatically Acquired Insertion and Deletion Events from Paired End Sequencing Curr Protoc Bioinformatics 2015 52 15.7.1 15.7.12 PMC6097606 26678382
  34. [41]Raine KM ascatNgs: Identifying Somatically Acquired Copy-Number Alterations from Whole-Genome Sequencing Data Current Protocols in Bioinformatics John Wiley & Sons, Inc 2016 15.9.1 15.9.17 2016 PMC6097604 27930809
  35. [42]Campbell PJ Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing Nat Genet 2008 40 722 9 18438408 PMC2705838
  36. [43]Alexandrov L The Repertoire of Mutational Signatures in Human Cancer bioRxiv 2018 10.1101/322859 322859 · DOI
  37. [44]Alexandrov LB Nik-Zainal S Wedge DC Campbell PJ Stratton MR Deciphering Signatures of Mutational Processes Operative in Human Cancer Cell Rep 2013 3 246 259 23318258 PMC3588146
  38. [45]Durinck S Spellman PT Birney E Huber W Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt Nat Protoc 2009 4 1184 91 19617889 PMC3159387
  39. [46]GTEx Consortium Genetic effects on gene expression across human tissues Nature 2017 550 204 213 29022597 PMC5776756
  40. [47]Blokzijl F Janssen R van Boxtel R Cuppen E MutationalPatterns: comprehensive genome-wide analysis of mutational processes Genome Med 2018 10 33 29695279 PMC5922316

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Authors
Brunner, S. F., Roberts, N. D., Wylie, L. A., Moore, L., Aitken, S. J., Davies, S. E., Sanders, M. A., Ellis, P., Alder, C., Hooks, Y., Abascal, F., Stratton, M. R., Martincorena, I., Hoare, M., & Campbell, P. J.
Affiliations
  • Wellcome Sanger Institute (GB)
  • University of Cambridge (GB)
  • Erasmus MC (NL)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
Corresponding author
  • Hoare, Matthew
  • Campbell, Peter J.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2019-10-23
Volume
574
Issue
7779
Pages
538-542
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-019-1670-9
PMC
PMC6837891
OpenAlex
W2981329637
Cited by
393
References
5
Citations by year
2026: 46 · 2025: 48 · 2024: 53 · 2023: 48 · 2022: 72 · 2021: 73 · 2020: 50 · 2019: 3
FWCI
15.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • European Hematology Association (TRTH182)
  • Wellcome Trust (103858/Z/14/Z, 103858, 206194, WT088340MA)
  • Cancer Research UK (26813, 19924, S_3369, 21777, S_2454, 24032)
  • National Institute for Health and Care Research (CL-2019-14-003)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (171753, 180790)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (019.153LW.038)
  • Medical Research Council (MC_PC_12009)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
Keywords
liver cirrhosis, somatic mutations, clonal dynamics, hepatocytes, mutational signatures, chromothripsis, structural variants, mutational burden, hepatocellular carcinoma, synchronous tumors, regenerative nodules, liver fibrosis, chronic liver disease, clonal expansion
MeSH terms
Clone Cells, DNA Mutational Analysis, Fibrosis, Carcinoma, Hepatocellular, Humans, Liver, Male, Middle Aged, Mutation, Phylogeny, Stem Cells, Hepatocytes

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