PMS2中杂合子突变可引起遗传性非息肉性大肠癌(Lynch综合征)

作     者：Hendriks Y.M.C. Jagmohan-Changur S. Van Der Klift H.M. 赵天智 

作者机构：Department of Clinical Genetics K5-R Leiden University MedicalCenter POBox 9600 2300 RC Leiden NetherlandsDr. 

出 版 物：《世界核心医学期刊文摘（胃肠病学分册）》 (Core Journals in Gastroenterology)

年 卷 期：2006年第2卷第8期

页      面：22-23页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：遗传性非息肉性大肠癌 Lynch综合征 杂合子 Southern印迹杂交 突变 HNPCC 大肠癌患者 错配修复基因 免疫组化研究 MLH1 

摘      要：Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. Methods: We performed Southern blot analysis in 112 patients from MLH1- , MSH2- , and MSH6- negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer,we performed immunohistochemistry using antibodies against MLH1,MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. Results: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. Conclusions: We show that heterozygous truncatingmutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with Absent staining for the PMS2 protein.