Goldberg Yael, Kedar Inbal, Kariiv Revital, Halpern Naama, Plesser Morasha, Hubert Ayala, Kaduri Luna, Sagi Michal, Lerer Israela, Abeliovich Dvorah, Hamburger Tamar, Nissan Aviram, Goldshmidt Hanoch, Solar Irit, Geva Ravit, Strul Hana, Rosner Guy, Baris Hagit, Levi Zohar, Peretz Tamar
Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Kyriat Hadassah, POB 12000, 91120, Jerusalem, Israel,
Fam Cancer. 2014 Mar;13(1):65-73. doi: 10.1007/s10689-013-9675-2.
Lynch Syndrome is caused by mutations in DNA mismatch repair genes. Diagnosis is not always trivial and may be costly. Information regarding incidence, genotype-phenotype correlation, spectrum of mutations and genes involved in specific populations facilitate the diagnostic process and contribute to clinical work-up. To report gene distribution, mutations detected and co-occurrence of related syndromes in a cohort of Ashkenazi Jews in Israel. Patients were identified in dedicated high risk clinics in 3 medical centers in Israel. Diagnostic process followed a multi-step scheme. It included testing for founder mutations, tumor testing, gene sequencing and MLPA. Lynch Syndrome was defined either by positive mutation testing, or by clinical criteria and positive tumor analysis. We report a cohort of 75 Ashkenazi families suspected of Lynch Syndrome. Mutations were identified in 51/75 (68%) families: 38 in MSH2, 9 in MSH6, and 4 in MLH1. 37/51 (73%) of these families carried one of the 3 'Ashkenazi' founder mutations in MSH2 or MSH6. Each of the other 14 families carried a private mutation. 3 (6%) were large deletions. Only 20/51 (39%) families were Amsterdam Criteria positive; 42 (82%) were positive for the Bethesda guidelines and 9 (18%) did not fulfill any Lynch Syndrome criteria. We report C-MMRD and co-occurrence of BRCA and Lynch Syndrome in our cohort. Mutation spectra and gene distribution among Ashkenazi Jews are unique. Three founder Lynch Syndrome mutations are found in 73% families with known mutations. Among the three, MSH2 and MSH6 are the most common. These features affect the phenotype, the diagnostic process, risk estimation, and genetic counseling.
林奇综合征由DNA错配修复基因的突变引起。诊断并非总是轻而易举，且可能成本高昂。有关发病率、基因型-表型相关性、突变谱以及特定人群中涉及的基因等信息有助于诊断过程，并为临床检查提供帮助。报告以色列阿什肯纳兹犹太人群体中基因分布、检测到的突变以及相关综合征的共现情况。在以色列3个医疗中心的专门高危诊所中识别患者。诊断过程遵循多步骤方案。包括对始祖突变进行检测、肿瘤检测、基因测序和多重连接依赖探针扩增（MLPA）。林奇综合征通过阳性突变检测或临床标准及阳性肿瘤分析来定义。我们报告了75个疑似林奇综合征的阿什肯纳兹家族队列。在51/75（68%）的家族中鉴定出突变：MSH2中有38个，MSH6中有9个，MLH1中有4个。这些家族中的37/51（73%）携带MSH2或MSH6中的3种“阿什肯纳兹”始祖突变之一。其他14个家族中的每个家族都携带一个私人突变。3个（6%）是大片段缺失。只有20/51（39%）的家族符合阿姆斯特丹标准阳性；42个（82%）符合贝塞斯达指南阳性，9个（18%）不符合任何林奇综合征标准。我们报告了我们队列中的C-MMRD以及BRCA和林奇综合征的共现情况。阿什肯纳兹犹太人中的突变谱和基因分布是独特的。在73%已知突变的家族中发现了3种始祖林奇综合征突变。在这三种突变中，MSH2和MSH6最为常见。这些特征影响表型、诊断过程、风险评估和遗传咨询。
