Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Dallas, Texas.
Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Dallas, Texas; Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California.
Clin Gastroenterol Hepatol. 2020 Aug;18(9):1949-1960. doi: 10.1016/j.cgh.2020.02.049. Epub 2020 Mar 5.
BACKGROUND & AIMS: Somatic mosaicism, in which variants arise post-zygotically and are therefore not present in all cells in the body, may be an underestimated cause of colorectal cancer (CRC) and polyposis syndromes. We performed a systematic review to provide a comprehensive overview of somatic mosaicism in patients with CRC and polyposis syndromes.
We searched PubMed through March 2018 to identify reports of mosaicism in patients with CRC or polyposis syndromes. We divided the final set of studies into 3 subgroups describing APC mosaicism, mosaicism in other CRC susceptibility genes, and epigenetic mosaicism.
Of the 232 articles identified in our systematic search, 46 met the criteria for further analysis. Of these, 35 studies described mosaic variants or epimutations in patients with CRC or polyposis syndromes. Nineteen studies described APC mosaicism, comprising a total of 57 patients. Six described mosaicism in genes associated with familial CRC syndromes, such as Lynch and Cowden syndromes. Ten studies described epigenetic mosaicism, sometimes resulting from a germline variant (such as deletion of EPCAM).
We found that somatic mosaicism is underdiagnosed but critical for determining the clinical management of patients with de novo polyposis who possibly carry mosaic APC variants, and present a decision tree for the clinical management of these patients. Mosaicism in genes associated with susceptibility to CRC contributes to development of other familial CRC syndromes. Heritable epigenetic mosaicism is likely underestimated and could have a dominant pattern of inheritance. However, the inheritance of primary mosaic epimutations, without an underlying genetic cause, is complex and not fully understood.
体细胞镶嵌性是指在合子后发生的变异，因此不存在于体内所有细胞中，它可能是结直肠癌（CRC）和息肉病综合征的一个被低估的原因。我们进行了一项系统评价，以提供 CRC 和息肉病综合征患者体细胞镶嵌性的全面概述。
我们通过 2018 年 3 月在 PubMed 上进行了搜索，以确定报道 CRC 或息肉病综合征患者镶嵌性的报告。我们将最终的研究集分为 3 个亚组，描述 APC 镶嵌性、其他 CRC 易感性基因的镶嵌性和表观遗传镶嵌性。
在我们的系统搜索中，确定了 232 篇文章，其中 46 篇符合进一步分析的标准。其中，35 项研究描述了 CRC 或息肉病综合征患者的镶嵌变体或表观遗传突变。19 项研究描述了 APC 镶嵌性，共包括 57 例患者。6 项研究描述了与家族性 CRC 综合征（如 Lynch 和 Cowden 综合征）相关的基因镶嵌性。10 项研究描述了表观遗传镶嵌性，有时是由种系变异（如 EPCAM 缺失）引起的。
我们发现，体细胞镶嵌性的诊断不足，但对于确定可能携带 APC 镶嵌变体的新发息肉病患者的临床管理至关重要，并为这些患者的临床管理提供了决策树。与 CRC 易感性相关的基因镶嵌性有助于其他家族性 CRC 综合征的发展。遗传性表观遗传镶嵌性可能被低估，并且可能具有显性遗传模式。然而，原发性镶嵌表观遗传突变的遗传，没有潜在的遗传原因，是复杂的，尚未完全理解。
