可疑遗传性非息肉病性结直肠癌的hMLH1和hMSH2基因突变研究

目的比较分析符合国际诊断标准的遗传性非息肉病性结直肠癌（ＩＣＧＨＮＰＣＣ）家系和提出的可疑ＨＮＰＣＣ家系的分子特征的异同，建立可疑ＨＮＰＣＣ诊断标准并评价其应用价值。方法根据ＡｍｓｔｅｒｄａｍＨＮＰＣＣ诊断标准和作者提出的可疑ＨＮＰＣＣ诊断标准，分别收集得到２９个ＩＣＧ家系和３４个可疑家系。提取先证者的外周血基因组ＤＮＡ，应用ＰＣＲＳＳＣＰ和ＤＮＡ测序的方法进行ｈＭＬＨ１和ｈＭＳＨ２基因的突变筛选。结果２９个ＩＣＧ家系中有９个家系被检出含有ｈＭＬＨ１基因的种系突变，突变率为３１０％；３４个可疑家系中有１０个家系被检出含有ｈＭＬＨ１或ｈＭＳＨ２基因的突变，两个基因的突变率分别为２３５％和５９％。ＩＣＧ组和可疑组中两个基因总突变率之间差异无显著意义（Ｐ＞００５）。ｈＭＬＨ１基因同是两组家系中的主要相关基因。两组家系中，突变均较一致地分布于基因的后半部分，突变类型也极为相似，均以导致短缩蛋白的突变最为常见。结论ＩＣＧ组和可疑组在遗传背景上有着相似之处，对ＨＮＰＣＣ诊断标准有一定的临床应用价值，有助于ＨＮＰＣＣ家系的临床诊断。

Mutations of hMLH 1 and hMSH2 genes in suspected hereditary nonpolyposis colorectal cancer.

Objective To analyze the molecular characteristics of 29 ICGHNPCC families and 34 suspected HNPCC families. Methods Genomic DNAs were prepared from peripheral blood samples of probands for DNA test. PCRSSCP and DNA sequencing analysis were employed to screen the germline mutations of hMLH1 and hMSH2 genes. Results In 29 ICGHNPCC families, 9 mutations in the hMLH1 gene were detected, while no mutation was found in the hMSH2 gene. The total mutation rate was 31.0% (9/29). In 34 suspected HNPCC families, 8 mutations in the hMLH1 gene and 2 mutations in the hMSH2 gene were detected. The total mutation rate in this group was 29.4% (10/34), including hMLH1 gene 23.5% (8/34) and hMSH2 gene 5.9% (2/34). hMLH1 gene was proven to be the main responsible gene in both ICGHNPCC and suspected HNPCC families, and no obvious difference was found between the mutation rate in the two kinds of families (P>0.05). As for the mutation type and location, similar characteristics were also detected. Almost all mutations located in the latter half of both genes, and mutation leading to protein truncation was the commonest type. Conclusion The similarity of mutation rate, mutation type and mutation location between ICGHNPCC and suspected HNPCC suggested the similarity of molecular basis and genetic background between these two groups, and also strongly indicated our criteria for suspected HNPCC is reasonable, and useful in the clinical diagnosis and management of HNPCC.