Trichloroethylene exposure and specific somatic mutations in patients with renal cell carcinoma
Trichloroethylene exposure and specific somatic mutations in patients with renal cell carcinoma
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DOI：
10.1093/jnci/91.10.854
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发表时间：
1999-05-19
影响因子：
10.3
通讯作者：
Brüning, T
中科院分区：
文献类型：
--
作者：
Brauch, H;Weirich, G;Brüning, T
背景:肾细胞癌（RCC）的发展与遗传和环境因素有关——透明细胞RCC特异性的von Hippel-Lindau （VHL）肿瘤抑制基因突变，以及长期暴露于高剂量的三氯乙烯（TRI）（一种工业上重要的RCC溶剂）。我们通过分析暴露于高累积剂量TRI的RCC患者的VHL序列，研究了TRI暴露是否通过对VHL基因的特定突变效应产生RCC。方法：根据暴露时间、频率和暴露方式对44名已知工业暴露于TRI的RCC患者的暴露水平进行分类，从石蜡包埋组织中显微解剖正常组织和癌组织样本。从这些样本中分离DNA，通过聚合酶链反应分析、单链构象多态性分析、DNA测序和限制性内切酶切鉴定体细胞VHL突变。对照样本包括107名未暴露于TRI的患者的RCC DNA和97名健康受试者的淋巴细胞DNA。结果：44例tri暴露患者的rcc中有33例（75%）出现体细胞VHL突变。突变通常是多重的，并伴有杂合性的丧失，突变的数量与TRI暴露的严重程度之间存在关联。我们观察到一个特定的突变热点信用社的面纱核苷酸454 13(39%)的病人,这个突变出现在相邻non-neoplastic肾实质的四个病人,454核苷酸突变既不是任何信用社的病人中发现三曝光也不是在任何健康受试者,结论:我们的研究结果表明,碾压混凝土高,患者累积三暴露与一个独特的VHL基因突变模式。
Background: The development of renal cell carcinoma (RCC) has been associated with both genetic and environmental factors-with mutations in the von Hippel-Lindau (VHL) tumor suppressor gene for clear-cell RCC specifically and with long-term exposure to high doses of trichloroethylene (TRI), an industrially important solvent, for RCC generally, We investigated whether TRI exposure produces RCC through a specific mutational effect on the VHL gene by analyzing VHL sequences in the RCCs of patients exposed to high, cumulative doses of TRI, Methods: The level of exposure for each of 44 patients with RCC who had known industrial exposure to TRI was classified according to the duration, frequency, and mode of exposure, Samples of normal and cancerous tissues were microdissected from paraffin embedded tissue. DNA was isolated from these samples, and somatic VHL mutations were identified by polymerase chain reaction analysis, single-strand conformation polymorphism analysis, DNA sequencing, and restriction enzyme digestion. Control samples included RCC DNA from 107 patients without known TRI exposure and lymphocyte DNA from 97 healthy subjects. Results: RCCs of TRI-exposed patients showed somatic VHL mutations in 33 (75%) of 44 cases. The mutations were frequently multiple and accompanied by loss of heterozygosity, and there was an association between the number of mutations and the severity of TRI exposure. We observed a specific mutational hot spot at VEIL nucleotide 454 in the RCCs of 13 (39%) of the patients, and this mutation was present in adjacent non-neoplastic kidney parenchyma in four of these patients, The nucleotide 454 mutation was neither detected in any of the RCCs from patients without TRI exposure nor in any of the healthy subjects, Conclusion: Our results suggest that RCC in patients with high, cumulative TRI exposure is associated with a unique mutation pattern in the VHL gene.