Val384Asp错义突变在家族性胃癌患者中的检出及其致病分子机制  

Genotype frequencies of the Val384Asp missense mutation in the hMLH1 gene in patients with familial gastric cancer

作　　者：王德强[1] 周建农[1] 宋磊[1] 李苏平[2] 丁建华[2] 李金田[3] 马国建[3] 陈森清[3] 张晓梅[3] 

机构地区：[1]南京医科大学附属江苏省肿瘤医院普通外科,江苏省南京市210029 [2]南京医科大学附属江苏省肿瘤医院流行病学研究室,江苏省南京市210029 [3]南京医科大学附属江苏省肿瘤医院分子生物学研究室,江苏省南京市210029

出　　处：《世界华人消化杂志》2010年第16期1669-1675,共7页World Chinese Journal of Digestology

基　　金：江苏省自然科学基金资助项目;No.BK2007258~~

摘　　要：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.AIM： To investigate the etiological role of the missense mutation, Val384Asp, in the human mutL homolog 1 （hMLH1） gene in familial gastric cancer （FGC） based on a Chinesepopulation in Jiangsu Province. METHODS： A case-control study was conducted. One hundred newly diagnosed or suspected FGC patients and 180 healthy controls were included in the study. Peripheral white blood cells were obtained from all subjects for DNA extraction. The Val384Asp missense mutation was detected using PCR-based denaturing high-performance liquid chromatography （DHPLC） and verified by DNA sequencing. Bioinformatic software was then used to analyze the etiological mechanism of the Val384Asp missense mutation. RESULTS： About 5% healthy individuals were Val384Asp carriers. Significant differences were noted for the following comparisons： patients with newly diagnosed or suspected FGC vs healthy controls （OR = 2.84, 95%CI： 1.07-7.81, P 0.05）, patients with an onset age ≥ 50 vs healthy controls （P 0.05）, patients with precancerous disease history vs healthy controls （P 0.01）, and patients having a high-risk family history of GC vs healthy controls （P 0.05）. Bioinformatic analysis showed that the Val384Asp missense mutation might destroy the structure of hMLH1 protein and impair its function. Besides, the conversion of T→A may disrupt pre-mRNA splicing. CONCLUSION： The Val384Asp missense mutation may be associated with genetic susceptibility to FGC. Detection of the Val384Asp missense mutation may be able to help identify individuals with increased risk of FGC.

关 键 词：家族性胃癌 HMLH1基因 Val384Asp 

分 类 号：R735.2[医药卫生—肿瘤]