Brauch H, Weirich G, Hornauer M A, Störkel S, Wöhl T, Brüning T
Research Laboratory of the Women's Hospital Eppendorf, University of Hamburg, Germany.
J Natl Cancer Inst. 1999 May 19;91(10):854-61. doi: 10.1093/jnci/91.10.854.
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.
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.
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 VHL 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.
Our results suggest that RCC in patients with high, cumulative TRI exposure is associated with a unique mutation pattern in the VHL gene.
肾细胞癌（RCC）的发生与遗传和环境因素均有关——透明细胞肾细胞癌具体与冯·希佩尔-林道（VHL）肿瘤抑制基因突变有关，而肾细胞癌总体上与长期高剂量接触三氯乙烯（TRI，一种具有重要工业用途的溶剂）有关。我们通过分析高累积剂量接触TRI患者的肾细胞癌中VHL基因序列，研究TRI暴露是否通过对VHL基因产生特定突变效应而导致肾细胞癌。
44例已知有工业TRI暴露史的肾细胞癌患者，根据暴露持续时间、频率和方式对每位患者的暴露水平进行分类。从石蜡包埋组织中显微切割正常和癌组织样本。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测序和限制性酶切鉴定体细胞VHL突变。对照样本包括107例无已知TRI暴露患者的肾细胞癌DNA和97例健康受试者的淋巴细胞DNA。
接触TRI的患者的肾细胞癌中，44例中有33例（75%）出现体细胞VHL突变。这些突变常为多个，并伴有杂合性缺失，且突变数量与TRI暴露严重程度之间存在关联。我们在13例（39%）患者的肾细胞癌中观察到VHL基因第454位核苷酸处有一个特定的突变热点，其中4例患者的相邻非肿瘤性肾实质中也存在该突变。在无TRI暴露患者的任何肾细胞癌中以及任何健康受试者中均未检测到第454位核苷酸突变。
我们的结果表明，高累积TRI暴露患者的肾细胞癌与VHL基因独特的突变模式有关。
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