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[目的]探讨错配修复基因hMLH1和hMSH2启动子区CpG岛甲基化及第12外显子(exon12)突变与燃煤污染型地方性砷中毒发生发展乃至癌变的关系。[方法]以砷中毒患者110例为病例组,按临床诊断分为轻、中、重度组;按皮肤病理诊断分为非癌变组和癌变组。采用甲基化特异性聚合酶链反应(MSP)法检测其中105例砷中毒患者和82例对照人群外周血中hMLH1和hMSH2基因启动子区的甲基化情况;采用聚合酶链反应-单链构象多态性分析(PCR-SSCP)检测110例砷中毒患者和110例对照人群外周血中hMLH1和hMSH2基因exon12突变情况。[结果]①轻、中、重度组砷中毒患者hMSH2基因甲基化阳性率分别为11.76%、16.28%和32.14%,均明显高于对照组,重度组亦明显高于轻度组(P<0.05或P<0.01);癌变组患者hMLH1和hMSH2基因甲基化阳性率分别为11.11%和27.78%,均明显高于对照组(P<0.05);hMLH1和hMSH2基因甲基化阳性率均随临床病情和皮肤病变程度加重而增高(P<0.05或P<0.01)。②病例组和对照组均未发现hMLH1和hMSH2基因exon12突变。[结论]错配修复基因hMLH1和hMSH2启动子区甲基化是砷中毒发生发展乃至癌变的早期分子特征,亦可能是导致错配修复功能缺陷的主要方式之一。
[Objective] To investigate the relationship between CpG island methylation and exon12 mutation of mismatch repair gene hMLH1 and hMSH2 promoters and carcinogenesis in coal-fired pollution endemic arsenism. [Methods] Arsenic poisoning patients with 110 cases as the case group, according to clinical diagnosis is divided into mild, moderate and severe group; according to the skin pathology diagnosis is divided into non-cancerous group and cancerous group. The methylation-specific polymerase chain reaction (MSP) was used to detect the methylation of hMLH1 and hMSH2 promoter in peripheral blood of 105 patients with arsenism and 82 controls. Polymerase chain reaction-single strand Conformational polymorphism (PCR-SSCP) was used to detect the mutation of hMLH1 and hMSH2 gene exon12 in 110 arsenism patients and 110 control subjects. [Results] ① The positive rate of hMSH2 gene methylation in patients with mild, moderate and severe arsenism was 11.76%, 16.28% and 32.14%, respectively, which were significantly higher than those in the control group (P < 0.05 or P <0.01). The positive rates of hMLH1 and hMSH2 gene methylation in cancer group were 11.11% and 27.78%, respectively, which were significantly higher than those in control group (P <0.05). The positive rates of hMLH1 and hMSH2 gene methylation were Clinical conditions and skin lesions increased and increased (P <0.05 or P <0.01). ② No cases of hMLH1 and hMSH2 gene exon12 mutations were found in case group and control group. [Conclusion] Methylation of mismatch repair gene hMLH1 and hMSH2 promoters is an early molecular feature of arsenic poisoning and carcinogenesis. It may also be one of the main ways to cause defects in mismatch repair.