Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore.
Cancer Science Institute, National University of Singapore, Singapore.
Clin Colorectal Cancer. 2019 Dec;18(4):e324-e334. doi: 10.1016/j.clcc.2019.05.007. Epub 2019 Jun 7.
Although at least 5 genes are implicated in Lynch Syndrome (LS), up to 50% of suspected cases are owing to undefined genes. We utilized next generation sequencing (NGS) to characterize the mutation profile of patients with cancer (CA) suspected to have LS.
We enrolled 174 Asian patients with CA from our CA Genetics Clinic from 2000 to 2014 suspected to have LS, and obtained germline DNA for NGS using TruSight Cancer. Frameshift, nonsense, and known deleterious mutations were considered pathogenic. Polymorphisms ≤ 1% frequency in 1000 Genomes (Asian) were classified using established databases.
Of the 174 probands, 80.5% were Chinese, the median age at CA diagnosis was 45 years (range, 18-82 years), and 84.5% and 8.6% had colon and LS-like CA, respectively. Forty-seven of 100 evaluable colon CA probands had LS-like histopathologic features. Nineteen of 174 had family history fulfilling Amsterdam I/II Criteria, whereas the rest fulfilled Bethesda Guidelines. Thirty-one of 174 harbored pathogenic mutations with 10 in LS genes only, 20 in non-LS genes only, and 1 in both. Of the 11 with LS gene mutations, MLH1 was most commonly involved (n = 7), followed by MSH2, MSH6, and PMS2. Nine of 174 had pathogenic mutations diagnostic of alternative hereditary syndromes including 2 each in CDH1, APC, and BRCA1, and 1 each in BRCA2, SMAD4, and MUTYH. Ten unique mutations were detected in low-to-moderate penetrance genes: 6 individuals had a recurring novel KIT:c.2836C>T nonsense mutation (n = 3) or ERCC4:c.2169C>A nonsense mutation (n = 3) without LS gene mutation, which is of clinical interest.
In this Asian study, NGS proved to be feasible in screening for causative mutations in patients with CA suspected to have LS.
尽管至少有 5 个基因与林奇综合征（LS）有关，但多达 50%的疑似病例是由于未定义的基因引起的。我们利用下一代测序（NGS）来描述患有癌症（CA）且疑似 LS 的患者的突变谱。
我们从 2000 年至 2014 年在我们的 CA 遗传诊所招募了 174 名患有 CA 的亚洲患者，并用 TruSight Cancer 获得了用于 NGS 的种系 DNA。移码、无义突变和已知的有害突变被认为是致病性的。在 1000 个基因组（亚洲）中频率≤1%的多态性使用已建立的数据库进行分类。
在 174 名先证者中，80.5%为中国人，CA 诊断时的中位年龄为 45 岁（范围，18-82 岁），84.5%和 8.6%分别患有结直肠癌和 LS 样 CA。100 名可评估结直肠癌先证者中有 47 名具有 LS 样组织病理学特征。174 名患者中有 19 名具有符合阿姆斯特丹 I/II 标准的家族史，而其余患者符合贝塞斯达指南。31 名患者携带致病性突变，其中 10 名仅存在 LS 基因，20 名仅存在非 LS 基因，1 名同时存在 LS 和非 LS 基因。在 11 名携带 LS 基因突变的患者中，MLH1 最常受累（n=7），其次是 MSH2、MSH6 和 PMS2。174 名患者中有 9 名携带可诊断为其他遗传性综合征的致病性突变，包括 CDH1、APC 和 BRCA1 各 2 例，BRCA2、SMAD4 和 MUTYH 各 1 例。在低至中度外显率基因中检测到 10 个独特的突变：6 名个体具有复发性新的 KIT:c.2836C>T 无义突变（n=3）或 ERCC4:c.2169C>A 无义突变（n=3），但没有 LS 基因突变，这具有临床意义。
在这项亚洲研究中，NGS 被证明在筛选疑似 LS 的 CA 患者的致病突变方面是可行的。
