Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.
Nat Commun. 2022 May 17;13(1):2710. doi: 10.1038/s41467-022-29920-2.
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.
林奇综合征（LS）是一种常染色体显性疾病，由于 DNA 错配修复（MMR）基因的种系杂合突变，导致结直肠癌风险增加。尽管 LS 患者的癌症表现出较高的体细胞突变负担，但关于正常组织中的突变率以及对从正常细胞到癌细胞的轨迹的理解有限。在这里，我们对 10 名 LS 患者的正常和肿瘤上皮组织中的 152 个隐窝进行了全基因组测序。在正常组织中，突变过程和突变率的库与在野生型个体中发现的相似。鉴定出具有增加的突变负担和 MMR 缺陷相关突变特征的形态正常的结肠隐窝，这可能代表 LS 发病机制的非常早期阶段。肿瘤隐窝的系统发育树表明，每个肿瘤的最近祖先细胞已经 MMR 缺陷，并经历了多次克隆进化。这项研究表明具有种系 MMR 基因突变的上皮细胞的基因组稳定性，并突出了 LS 与其他结直肠癌易感性综合征在发病机制上的重要差异。
