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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 understand the role of Val384Asp missense mutation in hMLH1 gene in the pathogenesis of familial colorectal cancer. Methods: Thirty-three patients with new-onset familial colorectal cancer, 66 patients with sporadic colorectal cancer, and 66 patients with sporadic colorectal cancer were collected from January to December 2004 in a high incidence area of three digestive cancers in a 1:2 matched case-control study. Peripheral venous blood of healthy individuals was analyzed by PCR-DHPLC and DNA sequence analysis techniques to analyze the exon 12 of the hMLH1 gene; bioinformatics-related software was used to analyze Val384Asp. RESULTS: There was no significant difference in the detection rate of Val384Asp between patients with familial colorectal cancer and sporadic patients and normal controls (P>0.05). However, the detection rate was significantly higher in familial patients aged ≥50 years. Normal controls (P < 0.05), while the difference with sporadic patients was at a critical value (P = 0.051); bioinformatics-related software analysis showed that the 384th position of Val (Val) is a conservative in biological evolution The site, which is replaced by aspartic acid (Asp), may affect protein function; the transversion of the corresponding site gene sequence T→A may also affect the shear regulation. CONCLUSION: Val384Asp is not a genetic susceptibility factor for familial colorectal cancer, but it is closely related to the pathogenesis of older patients. A large sample study is needed to confirm it. The pathogenic mechanism of Val384Asp may be related to the influence of protein function and shear abnormalities. .