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目的:了解hMLH1基因Val384Asp错义突变在家族性胃癌发病中的作用及Val384Asp可能的致病分子机制.方法:于江苏省淮安、泰兴及金坛三个肿瘤高发地区行现场调查,收集到100例2004年新发家族性或疑似家族性胃癌患者、180例健康人的外周血,应用PCR-DHPLC和DNA序列分析技术检测细胞的DNA,分析hMLH1基因的第12外显子,检测Val384Asp错义突变.生物信息学方法进行蛋白三维模型构建以及结构和功能学分析.结果:家族性/疑似家族性胃癌患者Val384Asp检出率显著高于正常对照(OR=2.84,95%CI:1.07-7.81,P<0.05).分组分析显示,Val384Asp与胃癌相关癌前疾病有协同性(P<0.01),并在发病年龄≥50岁的患者中显著分布(P<0.05).此外,对胃癌家系进行患病风险的评估后,发现来自高风险家系的患者检出率较高(P<0.05).蛋白三维模型显示,Val384Asp可以引起氢键的改变,可能影响hMLH1蛋白局部构象.功能学分析显示,降低蛋白功能和影响剪切调控是Val384Asp可能的致病机制.结论:中国家族性胃癌家系中的Val384Asp携带者可能有更高的胃癌发病风险.
OBJECTIVE: To investigate the role of Val384Asp missense mutation in familial gastric cancer and the potential pathogenesis of Val384Asp in hMLH1 gene.Methods: Field investigation was conducted in three high-risk areas of Huai’an, Taixing and Jintan in Jiangsu Province, 100 cases were collected Peripheral blood samples of 180 newly diagnosed familial or suspected familial gastric cancer patients in 2004 were analyzed by PCR-DHPLC and DNA sequence analysis. The exon 12 of hMLH1 gene was analyzed to detect the Val384Asp missense mutation .Bioinformatics method was used to construct three-dimensional model of protein and to analyze its structure and function.Results: The detection rate of Val384Asp in familial / suspected familial gastric cancer was significantly higher than that in normal control (OR = 2.84, 95% CI: 1.07-7.81, P <0.05) .Analysis by grouping showed that Val384Asp was associated with gastric cancer-related precancerous lesions (P <0.01), and was significantly distributed in patients with age≥50 years (P <0.05) .In addition, (P <0.05) .Protein 3D model showed that Val384Asp can cause changes in hydrogen bonding, which may affect the local conformation of hMLH1 protein.Functional analysis showed that the decrease of White function and regulation is the effect of shear Val384Asp possible pathogenic mechanisms conclusion:. Val384Asp carriers Chinese pedigrees with familial gastric cancer might have a higher risk of gastric cancer.