Mutational landscape of normal epithelial cells in Lynch Syndrome patients

• DOI: 10.1038/s41467-022-29920-2
• Publication Date: 2022-05-17T10:09:46Z
• Authors: 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; Michael R. Stratton
• Keywords: Lynch Syndrome; Pathogenesis

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