修饰型微卫星不稳定性与散发结直肠癌p53基因点突变的相关性  

"Modification" type microsatellite instability is correlated with p53 mutation in sporadic colorectal cancer

作　　者：赵岩[1] 张涛[1] 张剑军[1] 郑志超[1] 赵宜良[1] 前原喜彦[2] 

机构地区：[1]沈阳,辽宁省肿瘤医院第三外科 [2]日本九州大学大学院医学研究院消化器综合外科

出　　处：《肿瘤研究与临床》2007年第z1期-,共5页Cancer Research and Clinic

基　　金：日本厚生省文部科学省肿瘤研究基金

摘　　要：目的 高频度微卫星不稳定性被认定为DNA错配修复缺陷的标志,但既往研究发现一个显著矛盾,即在高频度微卫星不稳定结直肠癌中,p53突变率较一般结直肠癌低.研究旨在确认该矛盾的存在并试图阐明其机制.方法 对180例散发结直肠癌采用高分辨率荧光标记微卫星分析法检测微卫星位点稳定性,PCR扩增直接测序检测p53突变.结果 微卫星不稳定性呈现修饰型和跳跃型两种变化.低频度微卫星不稳定性均呈现修饰型而无跳跃型变化;高频度微卫星不稳定性均检出了跳跃型变化,一部分也并存修饰型变化.微卫星不稳定与肿瘤部位及分化程度明显相关,p53突变与肿瘤分化明显相关.高频度微卫星不稳定肿瘤未检出p53突变,而低频度微卫星不稳定肿瘤p53突变率较高.结论 低频度微卫星不稳定性呈现的修饰型微卫星位点长度变化可能是DNA错配修复缺陷的表型;此表型与提高的碱基置换突变率有关.单纯DNA错配修复缺陷可能不足以导致微卫星不稳定性的跳跃型变化,高频度微卫星不稳定的真正原因仍有待阐明.Objective High frequency microsatellite instability(MSI-H)was considered to be the phenotype of DNA mismatch repair(MMR)deficiency.However,a contradiction was noticed that p53 mutation is reposed to be extremely rare in MSI-H tumors.The aim of the current study was to confirm and try to explain this a phenomenon.We have demonstrated a direct link between MMR model and"modification"type MSI,and suggested the new categorization system of MSI by quantification of MSI profile.Based on this categorization system we studied the relationship between MSI and mutation of p53 oncogene in colorectal cancer.Methods A series of 180 sporadic colorectal cancer cases were investigated for their microsatellite status and p53 mutations.High resolution fluorescent microsatellite instability analysis assay and direct sequencing were employed in this study.Results Two definite patterns of microsatellite instability were confirmed,i.e."modification" type and "jumping" type MSI. In colorectal cancer,low frequency microsatellite instability (MSI-L)cases all showed pure"modification"type,while"jumping"type MSI changes were confirmed in all MSI-H cases.MSI-H was related with proximal tumor location and poorly differentiated.p53 mutation rate was more frequent in well differentiated tumors.Interestingly.MSI-L tumor showed a 40% mutation rate which is similar with MSS tumor 41%,however,in MSI-H tumors no p53 mutation was confirmed.Conclusions We confirm in human colorectal cancers,the"modification"type MSI might be connected with MMR defection.The mechanism underlying MSI-H phenotype was supposed to be other than MMR deficiency.

关 键 词：微卫星不稳定性 DNA错配修复 基因 p53 突变 结直肠肿瘤 

分 类 号：R730.231.3[医药卫生—肿瘤]