结直肠腺瘤的微卫星不稳定状态与相关基因表达的研究  

Microsatellite Instability and Relative Gene Expressions in Sporadic and Familial Adenomatous Polyposis Adenomas

作　　者：程蕾[1] 王慧萍[2] 黄琼[1] 来茂德[1] 

机构地区：[1]浙江大学医学院病理教研室,杭州310006 [2]浙江大学医学院附属第一医院肾脏病中心,杭州310002

出　　处：《遗传》2004年第1期1-7,共7页Hereditas（Beijing)

基　　金：国家自然科学基金(No.39770297)~~

摘　　要：应用微切割-聚合酶链反应-单链长度多态性(PCR SSLP)的方法,检测59例62个结直肠腺瘤,包括散发性腺瘤及家族性腺瘤性息肉病(FAP)腺瘤在BAT26等16个微卫星基因座在结直肠腺瘤标本的微卫星不稳定性(MSI)状态;并应用免疫组织化学SP法检测β 连接素(β catenin)、TP53、BAX等的表达情况,初步探讨错配修复(MMR)基因在结直肠癌发生的早期即腺瘤阶段的作用及其意义。结果显示:(1)腺瘤16个基因座的总MSI发生率为14.4%;同一病人的不同腺瘤在某些相同的基因座表现出不同的MSI状态;(2)5例FAP病人均表现为MSI L,其中有3例在hMSH3基因座表现为MSI阳性;(3)β 连接素在腺瘤和腺癌细胞膜阳性率分别为42.9%和11.4%,表达差异有显著统计学意义(P<0.001);(4)TP53、D5S346、TCF4(A)9、TGFβRⅡ(GT)3、TGFβRⅡ(A)10等微卫星基因座的MSI改变与相应的免疫组织化学指标TP53、β 连接素、TGFβRⅡ等在腺瘤及腺癌中的阳性表达有密切关系。可以推断:(1)在结直肠癌发生发展的早期即腺瘤阶段即可表现微卫星不稳定性,腺瘤中存在1p染色体的改变、APC基因的改变及TGFβ信号转导途径的异常;(2)随着腺瘤向腺癌的进展,β 连接素的阳性着色由细胞膜转移至细胞内,而且胞浆阳性强度增加;可以推断腺瘤中APC β 联蛋白 TCF4信号转导途径的异常。In order to understand the role of mismatch repair (MMR) gene in colorectal carcinogenesis,microsatellite instability (MSI) status of 16 microsatellite loci of 62 adenomas from 59 patients,including sporadic and familial adeonmatous polyposis (FAP) adenomas were detected by microdissection-PCR-SSLP,and protein expressions of β -catenin,P53,and BAX,etc.were assayed by immunohistochemistry.Results were as following:(1)The overall MSI alteration rate of the 16 loci was 14.4%.Different adenomas from the same patient showed different microsatellite alterations at the same loci;(2)All of the five FAP patients were MSI-L,three of which showed MSI at the locus of hMSH3;(3)The membrane expression rate of β-catenin in adenomas and accompanied carcinomas was 42.9% and 11.4%,respectively (P<0.001);⑷Microsatellite alterations of the microsatellite loci of TP53,D5S346,TCF4(A)_9,TGFβRⅡ(GT)_3 and TGFβRⅡ(A)_(10) were associated with the changes of their protein expressions.It could be concluded the following:(1)Microsatellite instability existed even in the early stage (adenomas) of colorectal tumorigenesis.The alterations of chromosome 1p,APC genes,and the TGFβ signal transduction pathway could also be deduced;(2)In the progression of adenoma to carcinoma,the staining of β-catenin would be transferred from membrane to cytoplasm and then nucleus,and the cytoplasm stain was stronger in carcinoma than that in adenomas.The abnormality of the signal transduction pathway of APC-β-catenin-TCF4 could be concluded.

关 键 词：结肠直肠癌 腺瘤 免疫组织化学 微卫星不稳定性 

分 类 号：R735.3[医药卫生—肿瘤]