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

• 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

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.

我们检查了 232 个原发性散发性肾细胞癌 (RCC) 以及 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。截短突变主要（超过 70%）发生在散发性肾癌中，而错义突变在种系中更为常见。即使在低级别和/或低阶段透明细胞肾细胞癌中也检测到突变，这表明该基因的失活是肿瘤发生中的一个非常早期的事件。在 VHL 家族中，基因型-表型相关性研究表明，预计会导致 VHL 功能丧失的非错义突变与肾癌（如散发性肾细胞癌）的发生相关。这些数据表明，尽管体细胞和种系之间存在不同的突变机制，但 VHL 蛋白的总体破坏是散发性和遗传性透明细胞肾细胞癌发展中的关键分子遗传变化。我们还在散发性低级别神经胶质瘤中发现了体细胞 VHL 突变，表明该基因参与了一些神经胶质瘤的肿瘤发生。我们通过原位杂交检查了 VHL 基因表达，发现近端肾小管上皮（常见类型透明细胞肾癌的推定起源）显示出强烈的信号。

项目成果

Nagashima Y, Miyagi Y, Udagawa K, Taki A, Misugi K, Sakai N, Kondo K, Kaneko S, Yao M, and Shuin T: "Von Hippel-Lindau tumour suppressor gene. Localization of expression by in situ hybridization"J Pathol. 180. 271-274 (1996)

Nagashima Y、Miyagi Y、Udakawa K、Taki A、Misugi K、Sakai N、Kondo K、Kaneko S、Yao M 和 Shuin T：“Von Hippel-Lindau 肿瘤抑制基因。通过原位杂交进行表达定位”J Pathol

Masahiro Yao, et al.: "Molecular Genetics of the Kidnig Cancers" Gann Monognaph on Cancer Research. 46(発表予定). (1998)

Masahiro Yao 等人：“肾癌的分子遗传学”Gann Monognaph 癌症研究 46（待出版）。

Yoshida M, Ashida S, Kondo K, Kobayashi K, Kanno H, Shinohara N, Shitara N, Kishida T, Kawakami S, Baba M, Yamamoto I, Hosaka M, Shuin T, and Yao M: "Germ-line Mutation Analysis in Patients with Von Hippel-Lindau Disease in Japan: an Extended Study of 77

Yoshida M、Ashida S、Kondo K、Kobayashi K、Kanno H、Shinohara N、Shitara N、Kishida T、Kawakami S、Baba M、Yamamoto I、Hosaka M、Shuin T 和 Yao M：“生殖系突变分析

Kobayashi K et al.: "Microsatellite instability occurs infrequently in sporadic renal cell carcinoma"Oncol Rep,. 4. 941-944 (1997)

Kobayashi K 等人：“微卫星不稳定性在散发性肾细胞癌中很少发生”Oncol Rep，。

Yao M et al.: "Molecular genetics of the Kidney cancers ; Implication of the OML tumor suppressor gene"Monograph on Cancer Res,. 46. 205-214 (1999)

Yao M 等：“肾癌的分子遗传学；OML 肿瘤抑制基因的意义”Monograph on Cancer Res，。