Mutational landscape of normal epithelial cells in Lynch Syndrome patients

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 Tsui, Annie S. Y. Chan, Anthony K. W. Chan, Siu Lun Ho, Peter J. Campbell, Inigo Martincorena, Simon J. A. Buczacki, Siu Tsan Yuen, Suet Yi Leung () and Michael R. Stratton ()
Additional contact information
Bernard C. H. Lee: The University of Hong Kong, Queen Mary Hospital
Philip S. Robinson: Wellcome Sanger Institute
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
Michael R. Stratton: Wellcome Sanger Institute

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29920-2

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