CAJ | 학술논문

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.
목적 고빈도미위성불은정성피인정위DNA착배수복결함적표지,단기왕연구발현일개현저모순,즉재고빈도미위성불은정결직장암중,p53돌변솔교일반결직장암저.연구지재학인해모순적존재병시도천명기궤제.방법 대180례산발결직장암채용고분변솔형광표기미위성분석법검측미위성위점은정성,PCR확증직접측서검측p53돌변.결과 미위성불은정성정현수식형화도약형량충변화.저빈도미위성불은정성균정현수식형이무도약형변화;고빈도미위성불은정성균검출료도약형변화,일부분야병존수식형변화.미위성불은정여종류부위급분화정도명현상관,p53돌변여종류분화명현상관.고빈도미위성불은정종류미검출p53돌변,이저빈도미위성불은정종류p53돌변솔교고.결론 저빈도미위성불은정성정현적수식형미위성위점장도변화가능시DNA착배수복결함적표형;차표형여제고적감기치환돌변솔유관.단순DNA착배수복결함가능불족이도치미위성불은정성적도약형변화,고빈도미위성불은정적진정원인잉유대천명.
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.