von Hippel-Lindau gene mutations in N-nitrosodimethylamine-induced rat renal epithelial tumors.

BACKGROUND

Mutations in the von Hippel-Lindau (VHL) gene are common in human clear cell kidney cancers. Carcinogens in cigarette smoke, especially nitrosamines, are known to induce kidney tumors of a variety of histologic types in rodents--but with no evidence of VHL mutations; however, none of these tumors resembled human clear cell carcinomas. We examined N-nitrosodimethylamine-induced kidney tumors of the clear or mixed clear/granular cell type in Wistar rats to assess the presence of VHL mutations.

METHODS

Sections of eight clear or mixed clear/granular cell kidney tumors that had been formalin fixed and paraffin embedded were microdissected. DNA was extracted from the microdissected tissue, and exons 1-3 of the rat VHL gene were examined by use of polymerase chain reaction and cycle sequencing techniques.

RESULTS

Four VHL gene mutations (three G:C to A:T and one A:T to G:C) were detected in three of the tumors in contrast to no mutations in 40 previously reported rat kidney tumors of other histologic types (three of eight tumors versus none of 40; two-sided Fisher's exact test; P=.003). Only tumors showing prominent swollen clear cell cytology with a signet-ring appearance had VHL mutations.

CONCLUSIONS

To our knowledge, this is the first report of VHL mutations in kidney tumors after direct chemical exposure and provides a possible molecular pathway linking tobacco smoking to kidney cancer.