Bilateral renal-cell carcinoma associated with an acquired VHL mutation and long-term trichloroethylene exposure.
OBJECTIVE
The genetic basis for clear-cell renal carcinomas has been established in familial and many sporadic forms. Whether the latter can be induced by environmental carcinogens remains controversial, with concern over solvents such as trichloroethylene (TCE). To study this putative relationship, we analyzed the VHL gene from a patient with long-term TCE exposure.


METHODS
PCR amplification and sequencing of VHL exons 1 - 3 were performed on peripheral blood and tumor tissue.


RESULTS
The tumor alone had a previously undescribed mutation in exon 1 of the VHL gene: deletion of a cytidine residue at position 291 relative to the first ATG start codon of the wild-type sequence. This deletion causes a frameshift and predicts an altered protein sequence from position 98 onwards.


CONCLUSIONS
The affected amino acids are in the functionally important beta-domain of the VHL protein that is implicated in substrate binding for ubiquitylation, and we hypothesize the mutation lowers that affinity. There is loss of suppressor function when substrates such as hypoxia-inducible factor have impaired degradation: they accumulate and ultimately cause uncontrolled cell turnover. This association of a proposed occupational cause and occurrence of renal-cell carcinoma emphasizes the availability and use of VHL sequencing for both studying the pathophysiology of malignant transformation and potentially playing a clinical role in genetic counseling or risk assessment.
Wells
G M
GM
Division of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, FL, USA.
Schroth
W
W
Brauch
H
H
Ross
E A
EA
D002292:Carcinoma, Renal Cell / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D006801:Humans; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009392:Nephrectomy; D016273:Occupational Exposure / Q000009:adverse effects*; D012997:Solvents / Q000009:adverse effects*; D014057:Tomography, X-Ray Computed; D014241:Trichloroethylene / Q000009:adverse effects*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
D012997:Solvents; D014241:Trichloroethylene; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human