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Mutational landscape of normal epithelial cells in Lynch Syndrome patients

Author

Listed:
  • Bernard C. H. Lee

    (The University of Hong Kong, Queen Mary Hospital)

  • Philip S. Robinson

    (Wellcome Sanger Institute
    University of Cambridge)

  • Tim H. H. Coorens

    (Wellcome Sanger Institute)

  • Helen H. N. Yan

    (The University of Hong Kong, Queen Mary Hospital)

  • Sigurgeir Olafsson

    (Wellcome Sanger Institute)

  • Henry Lee-Six

    (Wellcome Sanger Institute)

  • Mathijs A. Sanders

    (Wellcome Sanger Institute)

  • Hoi Cheong Siu

    (The University of Hong Kong, Queen Mary Hospital)

  • James Hewinson

    (Wellcome Sanger Institute)

  • Sarah S. K. Yue

    (The University of Hong Kong, Queen Mary Hospital)

  • Wai Yin Tsui

    (The University of Hong Kong, Queen Mary Hospital)

  • Annie S. Y. Chan

    (The University of Hong Kong, Queen Mary Hospital)

  • Anthony K. W. Chan

    (The University of Hong Kong, Queen Mary Hospital)

  • Siu Lun Ho

    (The University of Hong Kong, Queen Mary Hospital)

  • Peter J. Campbell

    (Wellcome Sanger Institute)

  • Inigo Martincorena

    (Wellcome Sanger Institute)

  • Simon J. A. Buczacki

    (University of Oxford, Headington)

  • Siu Tsan Yuen

    (The University of Hong Kong, Queen Mary Hospital)

  • Suet Yi Leung

    (The University of Hong Kong, Queen Mary Hospital
    The University of Hong Kong)

  • Michael R. Stratton

    (Wellcome Sanger Institute)

Abstract

Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.

Suggested Citation

  • Bernard C. H. Lee & Philip S. Robinson & Tim H. H. Coorens & Helen H. N. Yan & Sigurgeir Olafsson & Henry Lee-Six & Mathijs A. Sanders & Hoi Cheong Siu & James Hewinson & Sarah S. K. Yue & Wai Yin Tsu, 2022. "Mutational landscape of normal epithelial cells in Lynch Syndrome patients," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29920-2
    DOI: 10.1038/s41467-022-29920-2
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    References listed on IDEAS

    as
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