Molecular Genetic Study of the VHL Tumor Suppressor Gene in Human Renal Cell Carcinoma

人肾细胞癌VHL抑癌基因的分子遗传学研究

基本信息

批准号：
08671829
负责人：
YAO Masahiro
金额：
$ 1.41万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671829/
关键词：
VHL gene renal cell carcinoma tumor suppressor mutation

项目摘要

We have examined 232 primary sporadic renal cell carcinomas (RCCs) as well as 77 Japanese VHL families for VHL gene mutations. Mutation of the VHL gene was found in 56% of the clear-cell subtype RCCs and 73% of the VHL families. Truncating mutations were predominantly (more than 70%) in sporadic renal carcinomas, while missense mutations were more common in germ-lines. Mutations were detected even in low grade and/or low stage clear cell RCCs, suggesting that the inactivation of the gene is a very early event in the tumorigenesis. In VHL families, genotype-phenotype correlation study suggested non-missense mutations predicted to result in the loss of VHL function were associated with the occurrence of renal carcinoma like in sporadic RCCs. These data suggested, in spite of the different mutational mechanisms between somatic and germ-lines, gross disruption of the VHL protein is the critical molecular genetic change in the development of clear-cell RCCs both in sporadic and hereditary forms. We also found somatic VHL mutations in sporadic low grade gliomas, suggesting this gene is involved in tumorigenesis of some of glial tumors. We examined VHL gene expression by in situ hybridization, and found that the proximal tubular epithelium, the putative origin of the common type of clear cell renal carcinoma, showed intense signal.

我们已经检查了232个原发性零星肾细胞癌（RCC）以及77个日本VHL家族进行VHL基因突变。在56％的透明细胞亚型RCC和73％的VHL家族中发现了VHL基因的突变。在零星的肾癌中，截短突变主要是（超过70％），而错义突变在细菌线中更为常见。即使在低级和/或低阶透明细胞RCC中也检测到突变，这表明该基因的失活是肿瘤发生中的早期事件。在VHL家族中，基因型 - 表型相关研究表明，预测会导致VHL功能丧失的非松散突变与肾癌的发生有关，例如零星RCC中。这些数据表明，尽管体细菌和细菌之间存在不同的突变机制，但VHL蛋白的严重破坏是零星和遗传形式的透明电池RCC的发展中的关键分子遗传变化。我们还发现散发性低级神经胶质瘤中的体细胞VHL突变，表明该基因参与了一些神经胶质肿瘤的肿瘤发生。我们通过原位杂交检查了VHL基因表达，发现近端管状上皮是透明细胞肾癌的普通类型的推定起源，显示出强烈的信号。