Somatic aberrations of mismatch repair genes as a cause of microsatellite-unstable cancers
Somatic aberrations of mismatch repair genes as a cause of microsatellite-unstable cancers
复制标题
DOI：
10.1002/path.4419
复制
发表时间：
2014-12-01
影响因子：
7.3
通讯作者：
Dinjens, Winand N. M.
中科院分区：
文献类型：
--
作者：
Geurts-Giele, Willemina R. R.;Leenen, Celine H. M.;Dinjens, Winand N. M.
Lynch综合征（LS）是由错配修复（MMR）基因的种系突变引起的，导致微卫星不稳定肿瘤。大约35%的疑似LS （sLS）患者的种系MMR基因突变检测呈阴性，阻碍了LS的结结性诊断。本研究的目的是研究生殖系MMR基因突变阴性的sLS患者微卫星不稳定结直肠癌和子宫内膜癌的体细胞MMR基因畸变。疑似LS病例来自回顾性临床遗传学诊断队列和荷兰一项前瞻性多中心人群研究。总共有40例sLS患者（男/女20/20，中位年龄57岁）的微卫星不稳定肿瘤通过下一代测序筛选体细胞MMR基因突变。此外，我们还研究了这些肿瘤以及68例ls相关肿瘤和27例MLH1启动子超甲基化的微卫星不稳定肿瘤中受影响的MMR基因的杂合性缺失（LOH）。在sLS病例中，5/40（13%）的肿瘤有两种致病性体细胞突变，16/40（40%）的肿瘤有（可能的）致病性突变和LOH。总体而言，受影响的MMR基因位点的LOH在24/39（62%）具有信息丰富的LOH标记的肿瘤中观察到。LS病例和MLH1启动子超甲基化的肿瘤中，分别有39/61（64%）和2/21（10%）的肿瘤表现为LOH。没有种系MMR基因突变的sLS患者的微卫星不稳定肿瘤中有一半有两个（可能）有害的体细胞MMR基因畸变，表明它们是散发性的。因此，我们主张将MMR基因的体细胞突变和LOH分析加入到LS的分子诊断工作流程中。版权所有(c) 2014大不列颠和爱尔兰病理学会。约翰·威利父子有限公司出版
Lynch syndrome (LS) is caused by germline mutations in mismatch repair (MMR) genes, resulting in microsatellite-unstable tumours. Approximately 35% of suspected LS (sLS) patients test negative for germline MMR gene mutations, hampering conclusive LS diagnosis. The aim of this study was to investigate somatic MMR gene aberrations in microsatellite-unstable colorectal and endometrial cancers of sLS patients negative for germline MMR gene mutations. Suspected LS cases were selected from a retrospective Clinical Genetics Department diagnostic cohort and from a prospective multicentre population-based study on LS in The Netherlands. In total, microsatellite-unstable tumours of 40 sLS patients (male/female 20/20, median age 57 years) were screened for somatic MMR gene mutations by next-generation sequencing. In addition, loss of heterozygosity (LOH) of the affected MMR genes in these tumours as well as in 68 LS-associated tumours and 27 microsatellite-unstable tumours with MLH1 promoter hypermethylation was studied. Of the sLS cases, 5/40 (13%) tumours had two pathogenic somatic mutations and 16/40 (40%) tumours had a (likely) pathogenic mutation and LOH. Overall, LOH of the affected MMR gene locus was observed in 24/39 (62%) tumours with informative LOH markers. Of the LS cases and the tumours with MLH1 promoter hypermethylation, 39/61 (64%) and 2/21 (10%) tumours, respectively, demonstrated LOH. Half of microsatellite-unstable tumours of sLS patients without germline MMR gene mutations had two (likely) deleterious somatic MMR gene aberrations, indicating their sporadic origin. Therefore, we advocate adding somatic mutation and LOH analysis of the MMR genes to the molecular diagnostic workflow of LS. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd