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MUTATIONS IN THE VHL GENE FRIOM POTASSIUM BROMATE-INDUCED RAT CLEAR CELL RENAL TUMORS
Citation:
Shiao, Y. H., S. I. Kamata, L. M. Li, M. J. Hooth, A B. DeAngelo, L. M. Anderson, AND D C. Wolf. MUTATIONS IN THE VHL GENE FRIOM POTASSIUM BROMATE-INDUCED RAT CLEAR CELL RENAL TUMORS. CANCER LETTERS 187(1-2):207-214, (2002).
Description:
Potassium bromate (KBrO3) is a rat renal carcinogen and a major drinking water disinfection by-product in water disinfected with ozone. Clear cell renal tumors, the most common form of human renal epithelial neoplasm, are rare in animals but are inducible by KBrO3 in F344 rats. Detection of cytoplasmic periodic acid-Schiff-positive granules in clear cell tumors confirms that the tumor type is morphologically similar to its human counterpart. Mutation in the coding region of the von Hippel-Lindau (VHL) gene is frequently detected in human clear cell renal carcinomas. Detection of VHL mutations in KBrO3-induced rat renal tumors could enhance the relevancy of these rat renal tumors for human health risk assessment. Formalin-fixed paraffin-embedded control tissues and renal tumors from male F344 rats exposed to KBrO3 in the drinking water for 2 years were examined microscopically and were microdissected for DNA extraction. The coding sequence and a promoter region of the VHL gene were examined by polymerase chain reaction-single strand conformation polymorphism and/or DNA sequencing. Two of 9 clear cell renal tumors carried the same C to T mutation at the core region of the Sp1 transcription factor binding motif in the VHL promoter and one of 4 untreated animals had C to T mutation outside the highly-conserved core region. Mutation in the VHL coding sequence was only detected in one tumor. No VHL mutations were observed in 3 chromophilic tumors. KBrO3-induced rat renal tumors are morphologically similar to their human counterpart but the genetic basis of tumorigenesis is different.