Okkels Henrik, Lagerstedt-Robinsson Kristina, Wikman Friedrik P, Hansen Thomas V O, Lolas Ihab, Lindberg Lars Joachim, Krarup Henrik B
Section of Molecular Diagnostics, Department of Clinical Chemistry, Aalborg University Hospital, Aalborg, Denmark.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Genet Test Mol Biomarkers. 2019 Sep;23(9):688-695. doi: 10.1089/gtmb.2018.0316. Epub 2019 Aug 21.
Hereditary nonpolyposis colon cancer (HNPCC) and Lynch syndrome (LS) are characterized by defects in the mismatch repair (MMR) system, which protects the integrity of the genome. Pathogenic variants in four MMR genes (, , , and ) are responsible for LS, an autosomal, dominant hereditary disease that occurs with a frequency of 2-5% among all colorectal cancer cases. It has been estimated that ∼2-5% of all pathogenic variants found in the four MMR genes in LS cases are detected in the gene. An overview of detected variants is presented here. Long-range (LR) polymerase chain reaction (PCR) and multiplex ligation probe amplification (MLPA) assays were used to detect variants in ∼1500 probands. In a subset of the probands, pathogenic variants were detected by next-generation sequencing, and all detected variants were confirmed by LR-PCR combined with an MLPA assay. A summary of mutation analyses performed on colon cancer patients from molecular diagnostic laboratories in Denmark and Sweden is presented. By screening ∼1500 HNPCC probands, a total of 40 different variants were detected in 71 probands (5%); 20 variants were classified as pathogenic (C5), 2 variants as likely pathogenic (C4), 15 variants as variants of unknown significance (VUSs) (C3), 1 variant as likely benign (C2), and 2 variants as benign (C1). In total, 22/71 (31%) of the probands carried a pathogenic sequence variant. Among the probands with isolated loss of pPMS2 expression, the fraction of pathogenic variants was 20/35 (55%). Approximately 5% of the probands found in the Danish and Swedish populations presented here carried a variant. In this study, six novel pathogenic variants and seven VUSs are reported.
遗传性非息肉病性结直肠癌（HNPCC）和林奇综合征（LS）的特征是错配修复（MMR）系统存在缺陷，该系统可保护基因组的完整性。四个MMR基因（ 、 、 和 ）中的致病变异导致LS，这是一种常染色体显性遗传性疾病，在所有结直肠癌病例中的发生率为2 - 5%。据估计，在LS病例中四个MMR基因发现的所有致病变异中，约2 - 5%在 基因中被检测到。此处展示了检测到的变异概述。使用长程（LR） 聚合酶链反应（PCR）和 多重连接探针扩增（MLPA）检测法在约1500名先证者中检测 变异。在一部分先证者中，通过下一代测序检测到致病 变异，所有检测到的变异均通过LR-PCR结合MLPA检测法进行确认。展示了对来自丹麦和瑞典分子诊断实验室的结肠癌患者进行的 突变分析总结。通过筛查约1500名HNPCC先证者，在71名先证者（5%）中总共检测到40种不同的 变异；20种变异被分类为致病（C5），2种为可能致病（C4），15种为意义未明变异（VUSs）（C3），1种为可能良性（C2），2种为良性（C1）。总共，22/71（31%）的先证者携带致病序列变异。在仅表现出pPMS2表达缺失的先证者中，致病变异的比例为20/35（55%）。此处展示的丹麦和瑞典人群中约5%的先证者携带 变异。在本研究中，报告了6种新的致病变异和7种VUSs。
