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Novel mutations of the von Hippel‐Lindau tumor‐suppressor gene and rare DNA hypermethylation in renal‐cell carcinoma cell lines of the clear‐cell type
Author(s) -
Meyer Alexander J.,
Hernandez Ana,
Florl Andrea R.,
Enczmann Jürgen,
Gerharz ClausDieter,
Schulz Wolfgang A.,
Wernet Peter,
Ackermann Rolf
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(20000901)87:5<650::aid-ijc5>3.0.co;2-3
Subject(s) - renal cell carcinoma , cancer research , tumor suppressor gene , dna methylation , gene , cell , clear cell renal cell carcinoma , dna , biology , pathology , medicine , carcinogenesis , genetics , gene expression
Renal‐cell carcinoma (RCC) is the most common neoplasm of the kidney, accounting for about 3% of all adult malignancies. Histopathologically, 80% of all cases can be classified as clear‐cell RCC. Of these, approximately 55% to 70% are associated with mutations in the von Hippel‐Lindau (VHL) tumor‐suppressor gene. Here, new mutations of the VHL gene were defined by the use of temperature gradient gel electrophoresis and subsequent sequencing. In addition, DNA hypermethylation, an alternative mechanism of VHL gene silencing, was evaluated by methylation‐specific PCR. Twenty‐six clear‐cell, 3 chromophilic, and 2 chromophobic RCC cell lines were analyzed. Among the clear‐cell RCC cell lines tested, 12 (47%) contained 13 mutations overall: 8 (62%) in exon 1, 3 (23%) in exon 2, and 2 (15%) in exon 3. Ten of these mutations have thus far not been described. All single base pair changes were transversions. Six mutations led to alteration of a single amino acid. Seven mutations generated a frameshift or a stop codon. One cell line contained a complex duplication of 36 bp. All cell lines with mutations showed loss of heterozygosity in the VHL gene. No mutations could be detected in the chromophilic or chromophobic RCC samples. Significant hypermethylation was not observed in any of the cell lines. These data provide further evidence that distinct mutations in the VHL gene are a characteristic feature of clear‐cell RCC. In contrast, hypermethylation of the gene is probably a rare event. The high frequency of transversion mutations suggests a role for exogenous carcinogens in the etiology of clear‐cell RCCs. Int. J. Cancer 87:650–653, 2000. © 2000 Wiley‐Liss, Inc.