Daum Ondřej, Beneš Zdeněk, Hadravský Ladislav, Stehlík Jan, Cerná Kateřina, Dušek Martin, Kokošková Bohuslava, Michal Michal
Cesk Patol. 2014 Jan;50(1):18-24.
Lynch syndrome (formerly hereditary non-polyposis colorectal cancer) is the most common familial colorectal cancer syndrome with a known molecular genetic background. The syndrome is caused by a germline mutation of one of the genes encoding mismatch repair (MMR) proteins that are responsible for DNA replication errors repair. Impaired function of these proteins leads to microsatellite instability (MSI) and forms a suitable background for the development and progression of tumors, mainly colorectal cancer. Traditionally, Lynch syndrome was regarded to be responsible for 2 % of all cases of colorectal cancer, however recent estimates reach even 5 %. Due to this relatively high frequency, familial occurence, the absence of the premorbid phenotype and the development of malignant tumors during the productive years of life, the correct diagnosis becomes not only a medical, but also a socioeconomical problem. Unfortunately, clinical means of diagnostics of Lynch syndrome (like the Amsterdam criteria and Bethesda guidelines) lack sensitivity. It was shown that predictive models based on histological signs of MSI are more sensitive than the clinical criteria used to detect patients suspicious of Lynch syndrome. Of all MSI-H colorectal cancers, 1/5 is caused by Lynch syndrome, the rest being only sporadic cancers caused by epigenetic inactivation of a MMR protein. To rule out the sporadic cases, molecular genetic investigation of the BRAF gene and methylation analysis of MLH1 is used in the diagnostic workup of Lynch syndrome. The suspicion of Lynch syndrome, based on the results of the assortment of diagnostic methods mentioned above, should be proven by detection of a germline mutation of an MMR gene in peripheral blood, and followed by screening of family members, which is a necessary condition for efficient prevention.
林奇综合征（以前称为遗传性非息肉病性结直肠癌）是最常见的具有已知分子遗传学背景的家族性结直肠癌综合征。该综合征由编码错配修复（MMR）蛋白的基因之一的种系突变引起，这些蛋白负责修复DNA复制错误。这些蛋白功能受损会导致微卫星不稳定性（MSI），并为肿瘤（主要是结直肠癌）的发生和发展形成合适的背景。传统上，林奇综合征被认为占所有结直肠癌病例的2%，然而最近的估计甚至达到了5%。由于其相对较高的发病率、家族聚集性、缺乏病前表型以及在生育年龄发生恶性肿瘤，正确诊断不仅成为一个医学问题，而且也是一个社会经济问题。不幸的是，林奇综合征的临床诊断方法（如阿姆斯特丹标准和贝塞斯达指南）缺乏敏感性。研究表明，基于MSI组织学特征的预测模型比用于检测疑似林奇综合征患者的临床标准更敏感。在所有MSI-H结直肠癌中，五分之一由林奇综合征引起，其余仅为由MMR蛋白表观遗传失活导致的散发性癌症。为了排除散发性病例，在林奇综合征的诊断检查中使用BRAF基因的分子遗传学研究和MLH1的甲基化分析。基于上述各种诊断方法的结果怀疑林奇综合征，应通过检测外周血中MMR基因的种系突变来证实，然后对家庭成员进行筛查，这是有效预防的必要条件。
