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 (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.
Brüning
T
T
Institut für Arbeitsphysiologie, Universität Dortmund, Germany.
Weirich
G
G
Hornauer
M A
MA
Höfler
H
H
Brauch
H
H
D000368:Aged; D015197:Carcinogenicity Tests; D002292:Carcinoma, Renal Cell / Q000139:chemically induced / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D006801:Humans; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D016273:Occupational Exposure; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014241:Trichloroethylene / Q000009:adverse effects*
D014241:Trichloroethylene