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Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Author

Listed:
  • Philip S. Robinson

    (Wellcome Sanger Institute
    University of Cambridge)

  • Laura E. Thomas

    (Swansea University)

  • Federico Abascal

    (Wellcome Sanger Institute)

  • Hyunchul Jung

    (Wellcome Sanger Institute)

  • Luke M. R. Harvey

    (Wellcome Sanger Institute)

  • Hannah D. West

    (Cardiff University School of Medicine)

  • Sigurgeir Olafsson

    (Wellcome Sanger Institute)

  • Bernard C. H. Lee

    (Wellcome Sanger Institute
    The University of Hong Kong, Queen Mary Hospital)

  • Tim H. H. Coorens

    (Wellcome Sanger Institute)

  • Henry Lee-Six

    (Wellcome Sanger Institute)

  • Laura Butlin

    (Cardiff University School of Medicine)

  • Nicola Lander

    (Cardiff University School of Medicine)

  • Rebekah Truscott

    (Cardiff University School of Medicine)

  • Mathijs A. Sanders

    (Wellcome Sanger Institute
    Erasmus University Medical Centre)

  • Stefanie V. Lensing

    (Wellcome Sanger Institute)

  • Simon J. A. Buczacki

    (University of Oxford)

  • Rogier Hoopen

    (University of Cambridge)

  • Nicholas Coleman

    (University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust)

  • Roxanne Brunton-Sim

    (Norfolk and Norwich University Hospital)

  • Simon Rushbrook

    (Norfolk and Norwich University Hospital
    University of East Anglia)

  • Kourosh Saeb-Parsy

    (University of Cambridge
    Cambridge Biomedical Campus)

  • Fiona Lalloo

    (Saint Mary’s Hospital)

  • Peter J. Campbell

    (Wellcome Sanger Institute)

  • Iñigo Martincorena

    (Wellcome Sanger Institute)

  • Julian R. Sampson

    (Cardiff University School of Medicine)

  • Michael R. Stratton

    (Wellcome Sanger Institute)

Abstract

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequence normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 4-fold in all individuals, except for one showing a 31-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C > A changes. Different mutation rates and signatures between individuals are likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31341-0
    DOI: 10.1038/s41467-022-31341-0
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