Renal cell carcinomas in trichloroethene(TRI) exposed persons are associated with somatic mutations in the von Hippel-Lindau (VHL) tumour suppressor gene
Renal cell carcinomas in trichloroethene(TRI) exposed persons are associated with somatic mutations in the von Hippel-Lindau (VHL) tumour suppressor gene
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DOI：
10.1007/s002040050394
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发表时间：
1997-03-01
影响因子：
6.1
通讯作者：
Brauch, H
中科院分区：
文献类型：
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作者：
Bruning, T;Weirich, G;Brauch, H
肾细胞癌（RCC）的发展是由于von Hippel-Lindau （VHL）肿瘤抑制基因的体细胞突变。最近的流行病学研究表明，高剂量和长期职业接触三氯乙烯（TRI）与肾细胞癌发病率增加有关。我们分析了23例具有极高TRI暴露职业史的RCC患者的肿瘤组织中VHL基因的体细胞突变。从肿瘤细胞微解剖中分离DNA，经聚合酶链反应（PCR）扩增，进行单链构象多态性（SSCP）分析和测序。迄今为止分析的所有23名TRI暴露者的RCC组织均显示VHL基因畸变，其中30%外显子1,44%外显子2,26%外显子3。与未暴露于tri的RCC患者中较低的VHL突变频率（33-55%）相比，这些结果表明，暴露于tri的RCC患者中VHL基因的突变频率特别高；通过序列分析，其中4个畸变已被证实为VHL突变。这一发现表明VHL基因是TRI诱导肾癌发生的易感和特异性靶点。此外，外显子2的频繁参与确定了这种致癌物的潜在“热点”。除了现有的流行病学研究外，现在的结果进一步证明，职业高度接触三氧化二氮会导致人类肾脏致癌性。
Renal cell carcinomas (RCC) develop as a consequence of somatic mutations of the von Hippel-Lindau (VHL) tumour suppressor gene. Recent epidemiological studies show that high and prolonged occupational exposures to trichloroethene (TRI) are associated with an increased incidence of RCC. Tumour tissues from 23 RCC patients with occupational histories of very high TRI exposure were analysed for somatic mutations within the VHL gene. DNA was isolated from microdissected tumour cells, amplified by polymerase chain reaction (PCR), and analysed in single strand conformation polymorphism (SSCP) and sequencing. RCC tissues of all 23 TRI exposed persons analysed thus far showed aberrations of the VHL gene, with 30% having aberrations in exon 1, 44% in exon 2, and 26% in exon 3. By comparison to much lower reported VHL mutation frequencies of 33-55% in TRI-unexposed RCC patients, these results indicate a specifically high mutation frequency at the VHL gene in TRI-exposed RCC patients; four of these aberrations have thus far been confirmed as VHL mutations by sequence analysis. This finding indicates the VHL gene being a susceptible and specific target in TRI induced renal carcinogenesis. Furthermore, the frequent involvement of exon 2 identifies potential 'hot spots' for this carcinogen. In addition to the available epidemiological studies the results are now further proof for human renal carcinogenicity induced by high occupational exposures to TRI.