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

我们检测了232例原发性散发性肾细胞癌（rcc）和77个日本VHL家族的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基因突变。截短突变在散发性肾癌中占主导地位（超过70%），而错义突变在生殖系中更为常见。即使在低级别和/或低阶段的透明细胞rcc中也检测到突变，这表明该基因的失活是肿瘤发生的早期事件。在VHL家族中，基因型-表型相关研究表明，预测导致VHL功能丧失的非错义突变与散发性rcc中肾癌样的发生相关。这些数据表明，尽管体细胞系和种系之间存在不同的突变机制，但VHL蛋白的严重破坏是散发性和遗传性透明细胞rcc发生的关键分子遗传变化。我们还在散发性低级别胶质瘤中发现了体细胞VHL突变，表明该基因参与了一些胶质瘤的肿瘤发生。我们通过原位杂交检测了VHL基因的表达，发现近端小管上皮（被认为是常见透明细胞肾癌的起源）显示出强烈的信号。

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.