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POTASSIUM BROMATE-INDUCED RAT CLEAR CELL RENAL TUMOR IS INDEPENDENT OF CODING REGION MUTATIONS IN THE VON HIPPEL- LINDAU GENE
Citation:
Shiao, Y. H., M. Hooth, L. M. Li, A B. DeAngelo, L. M. Anderson, AND D C. Wolf. POTASSIUM BROMATE-INDUCED RAT CLEAR CELL RENAL TUMOR IS INDEPENDENT OF CODING REGION MUTATIONS IN THE VON HIPPEL- LINDAU GENE. Presented at Society of Toxicology Annual Meeting, Philadelphia, PA, March 19-23, 2000.
Description:
Potassium bromate (KBr03) is a rat renal carcinogen and a major drinking water disinfection by-product from ozonization. While KBr03 is a human nephro- and neuro-toxicant, its carcinogenicity in humans is unknown. Clear cell renal tumors, the common form of human renal carcinomas, are rare in animals but can be induced by KBr03 in Fischer 344 rats. Alteration of the von Hippel-Lindau (VHL) gene is frequently observed in clear cell renal carcinomas in humans and has been associated with the same tumor type induced by N-nitrosodimethylamine in Wistar rats. Detection of VHL mutations in KBrO3-induced rat renal tumors would allow direct comparison of mutation spectra with those in humans, providing an indication of relevance for carcinogenicity of KBrO3 in human kidney. Formalin-fixed paraffin-embedded clear cell renal tumors from male Fischer 344 rats treated with KBr03 for 2 years in the drinking water and kidney samples from untreated control were microdissected for DNA extraction. The coding region and exon-intron boundaries of the VHL gene were examined by polymerase chain reaction, which was optimized to amplify fragmented DNA from archived tissues, and direct DNA sequencing. More than 90% of the DNA sequencing has been completed. No mutations were detected in any of 9 selected kidney tumors and 1 control. This suggests that induction of clear cell renal tumor by KBrO3 in Fischer 344 rats is not associated with mutations in the coding region of the VHL gene. Other VHL alterations, such as allele loss and methylation in the promoter region, have been reported in human clear cell renal carcinomas and are under investigation in these rat tumors in order to clarify the role of VHL in KBr03-induced rat renal tumorigenesis.