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目的探讨中国人遗传性非息肉病性结直肠癌(HNPCC)家系中hMLH1、hMSH2基因遗传性突变情况。方法取14个符合中国人HNPCC标准的HNPCC家系肿瘤先证者外周血DNA样本,聚合酶链反应扩增hMLH1、hMSH2基因共35个外显子,应用变性高效液相色谱技术(DHPLC)结合DNA测序法检测突变。结果14个家系中共发生41个大肠癌和19个肠外恶性肿瘤,其中胃癌是最常见的肠外恶性肿瘤类型。14个患者中检测到分属于9个家系的12个遗传性单个碱基改变,其中8%为无义突变,25%为错义突变,其余42%为单核苷酸多态,17%为内含子区的单碱基改变,8%为同义突变。结论(1)应用DHPLC成功检测到hMLH1、hMSH2基因杂合性突变。(2)符合中国人HNPCC标准家系约有1/3可检出hMLH1、hMSH2基因遗传杂合性突变,其中错义突变较多见。
Objective To investigate the genetic mutation of hMLH1 and hMSH2 in Chinese hereditary nonpolyposis colorectal cancer (HNPCC) pedigrees. Methods Fourteen DNA samples of HNPCC family members who had Chinese HNPCC pedigree were included in this study. 35 exons of hMLH1 and hMSH2 genes were amplified by polymerase chain reaction (PCR) and denatured high performance liquid chromatography (DHPLC) combined with DNA Sequencing to detect mutations. Results A total of 41 colorectal carcinomas and 19 extraintestinal malignancies were found in 14 pedigrees, of which gastric cancer was the most common type of extraintestinal malignant tumor. Of the 14 patients, 12 hereditary single nucleotide changes were detected in 9 pedigrees, of which 8% were nonsense mutations, 25% were missense mutations and the remaining 42% were single nucleotide polymorphisms and 17% were Intron region single base change, 8% synonymous mutations. Conclusions (1) The heterozygous mutation of hMLH1 and hMSH2 gene was successfully detected by DHPLC. (2) About one third of HNPCC pedigrees in Chinese were detected heterozygous heterozygous mutations of hMLH1 and hMSH2 genes, of which missense mutations were more common.