错配修复基因hMLH1突变Val384Asp在家族性大肠癌发病中的作用  

Etiological role of Val384Asp in hMLH1 gene in familial colorectal cancer

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

机构地区：[1]南京医科大学附属江苏省肿瘤医院普外科,江苏南京210009 [2]南京医科大学附属江苏省肿瘤医院分子生物学实验室,江苏南京210009

出　　处：《南京医科大学学报（自然科学版）》2010年第1期1-6,共6页Journal of Nanjing Medical University(Natural Sciences)

基　　金：江苏省自然科学基金(BK2007258)

摘　　要：目的:了解hMLH1基因Val384Asp错义突变在家族性大肠癌发病中的作用。方法:以1∶2配对病例对照研究设计,于2004年1～12月在江苏省3个消化道肿瘤高发地区收集新发家族性大肠癌患者33例、散发性大肠癌患者66例及66例健康人的外周静脉血,应用PCR-DHPLC和DNA序列分析技术,分析hMLH1基因的第12外显子;生物信息学相关软件分析Val384Asp。结果:家族性大肠癌患者的Val384Asp检出率与散发性患者间以及正常对照间差异无统计学意义(P>0.05);但在≥50岁的高龄家族性患者中的检出率显著高于正常对照(P<0.05),而与散发性患者间的差异处于临界值(P=0.051);生物信息学相关软件分析显示,第384位的撷氨酸(Val)是生物进化中的一个保守位点,其被天冬氨酸(Asp)替代可能影响蛋白质功能;相应位点基因序列T→A的颠换也可能影响剪切调控。结论:Val384Asp不是家族性大肠癌的遗传易感因素,但与其中的高龄患者的发病有密切关系,尚需进一步的大样本研究证实;Val384Asp的致病机制可能与影响蛋白功能及剪切异常有关。Objective：To investigate the etiological role of the Val384Asp in hMLHI gene in familial colorectal cancer. Methods：a 1：2 matched case-control study was conducted in three of the high gastrointestinal cancer incidence areas in Jiangsu. Subjects included 33 familial colorectal cases,66 sporadic cases and 66 health individual controls. Peripheral white blood cell DNA was obtained from all subjects, hMLH1 gene T1151A was analysed using a PCR-based DHPLC,and the existence of Val384Asp was verified by DNA sequencing. Bioinformatics software was used to analysis the etiological mechanism of Val384Asp. Results：There was no statistical difference in the genotype frequencies of the Val384Asp between the cases and controls （P 〉 0.05）. The significant difference existed between the old patients （onset age≥50）with familial colorectal cancer and the health controls （P 〈 0.05）;Bioinformatics software analysis showed Va1384Asp was a conserved variant between species and may impair hMLHI protein function;the allete transverse of T→A may disrupt pre-mRNA splicing. Conclusion：These findings suggested that the Val384Asp may not be associated with genetic susceptibility to colorectal cancer in the genealogical members of familial colorectal cancer,but have a strong relationship with the morbidity of old patients in this group;and be associated with disrupting of protein function or pre-mRNA splicing.

关 键 词：结肠直肠肿瘤 家族性 HMLH1基因 错义突变 Val384Asp 

分 类 号：R365[医药卫生—病理学]