Lagerstedt-Robinson Kristina, Rohlin Anna, Aravidis Christos, Melin Beatrice, Nordling Margareta, Stenmark-Askmalm Marie, Lindblom Annika, Nilbert Mef
Department of Molecular Medicine and Surgery, Karolinska Institute and Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden.
Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, SE-41345 Gothenburg, Sweden.
Oncol Rep. 2016 Nov;36(5):2823-2835. doi: 10.3892/or.2016.5060. Epub 2016 Sep 1.
Lynch syndrome caused by constitutional mismatch‑repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.
由遗传性错配修复缺陷引起的林奇综合征是最常见的遗传性癌症综合征之一，患结直肠癌、子宫内膜癌、卵巢癌和尿路上皮癌的风险很高。林奇综合征由错配修复（MMR）基因即MLH1、MSH2、MSH6和PMS2的突变引起。经过20年对林奇综合征的遗传咨询和基因检测，我们汇编了瑞典的突变谱，旨在从人群角度了解不同MMR基因的贡献、各种类型的突变以及奠基者突变的影响。突变数据是在全国范围内从所有参与基因检测的实验室收集的。突变分析主要使用桑格测序和多重连接依赖探针扩增。在369个林奇综合征家族中总共鉴定出201个独特的疾病易感性MMR基因突变。这些突变在40%的家族中影响MLH1，36%影响MSH2，18%影响MSH6，6%影响PMS2。鉴定出了多种突变，剪接位点突变是MLH1中最常见的突变类型，移码突变在MSH2和MSH6中占主导。一个或几个外显子的大片段缺失在MLH1和MSH2的突变中占21%，在PMS2中占22%，但在MSH6中很少见（4%）。在66%的林奇综合征家族中鉴定出的变异是私有的，奠基者突变的影响有限，主要与一种芬兰奠基者突变有关，该突变占MLH1突变家族的15%。总之，瑞典林奇综合征的突变谱多样，三分之二的家族存在私有的MMR基因突变，国际公认的突变有显著贡献，奠基者突变的影响有限。
