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Somatic mutations and clonal dynamics in healthy and cirrhotic human liver

Author

Listed:
  • Simon F. Brunner

    (Wellcome Trust Sanger Institute)

  • Nicola D. Roberts

    (Wellcome Trust Sanger Institute)

  • Luke A. Wylie

    (Wellcome Trust Sanger Institute)

  • Luiza Moore

    (Wellcome Trust Sanger Institute)

  • Sarah J. Aitken

    (CRUK Cambridge Institute
    University of Cambridge, Addenbrooke’s Hospital)

  • Susan E. Davies

    (University of Cambridge, Addenbrooke’s Hospital)

  • Mathijs A. Sanders

    (Wellcome Trust Sanger Institute
    Erasmus University Medical Center)

  • Pete Ellis

    (Wellcome Trust Sanger Institute)

  • Chris Alder

    (Wellcome Trust Sanger Institute)

  • Yvette Hooks

    (Wellcome Trust Sanger Institute)

  • Federico Abascal

    (Wellcome Trust Sanger Institute)

  • Michael R. Stratton

    (Wellcome Trust Sanger Institute)

  • Inigo Martincorena

    (Wellcome Trust Sanger Institute)

  • Matthew Hoare

    (CRUK Cambridge Institute
    University of Cambridge, Addenbrooke’s Hospital)

  • Peter J. Campbell

    (Wellcome Trust Sanger Institute
    University of Cambridge)

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 genes1–7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, 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.

Suggested Citation

  • Simon F. Brunner & Nicola D. Roberts & Luke A. Wylie & Luiza Moore & Sarah J. Aitken & Susan E. Davies & Mathijs A. Sanders & Pete Ellis & Chris Alder & Yvette Hooks & Federico Abascal & Michael R. St, 2019. "Somatic mutations and clonal dynamics in healthy and cirrhotic human liver," Nature, Nature, vol. 574(7779), pages 538-542, October.
  • Handle: RePEc:nat:nature:v:574:y:2019:i:7779:d:10.1038_s41586-019-1670-9
    DOI: 10.1038/s41586-019-1670-9
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    Citations

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    Cited by:

    1. Ewart Kuijk & Onno Kranenburg & Edwin Cuppen & Arne Van Hoeck, 2022. "Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Philip S. Robinson & Laura E. Thomas & Federico Abascal & Hyunchul Jung & Luke M. R. Harvey & Hannah D. West & Sigurgeir Olafsson & Bernard C. H. Lee & Tim H. H. Coorens & Henry Lee-Six & Laura Butlin, 2022. "Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Tianyu Zhu & Huige Tong & Zhaozhen Du & Stephan Beck & Andrew E. Teschendorff, 2024. "An improved epigenetic counter to track mitotic age in normal and precancerous tissues," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Biancastella Cereser & Angela Yiu & Neha Tabassum & Lisa Del Bel Belluz & Sladjana Zagorac & Kenneth Russell Zapanta Ancheta & Rongrong Zhong & Cristian Miere & Alicia Rose Jeffries-Jones & Nina Moder, 2023. "The mutational landscape of the adult healthy parous and nulliparous human breast," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    5. Manako Yamaguchi & Hirofumi Nakaoka & Kazuaki Suda & Kosuke Yoshihara & Tatsuya Ishiguro & Nozomi Yachida & Kyota Saito & Haruka Ueda & Kentaro Sugino & Yutaro Mori & Kaoru Yamawaki & Ryo Tamura & Sun, 2022. "Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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