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Mutations in the VHL gene from potassium bromate-induced rat clear cell renal tumors
Yih-Horng Shiao1, Sonie I Kamata, Leeanne M Li
1Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD, USA.
Abstract:
Potassium bromate (KBrO(3)) 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 KBrO(3) in F344 rats. Detection of cytoplasmic periodic acid-Schiff-positive granules in clear cell tumors, indicative of glycogen accumulation, provides evidence of their biochemical similarity to human counterparts. 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 KBrO(3)-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 KBrO(3) 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 nine 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 four 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 three chromophilic tumors. KBrO(3)-induced rat renal tumors are morphologically similar to their human counterpart but the genetic basis of tumorigenesis is different.
Insights
Potassium bromate induces rat kidney tumors similar to human clear cell renal carcinomas. However, the genetic basis differs, with VHL gene promoter mutations found in rats, unlike common VHL coding mutations in humans.
Area of Science:
- Toxicology
- Carcinogenesis
- Molecular Biology
Background:
- Potassium bromate (KBrO3) is a carcinogen and a drinking water disinfection byproduct.
- Clear cell renal tumors, common in humans, are rare in animals but inducible by KBrO3 in F344 rats.
- VHL gene mutations are frequent in human clear cell renal carcinomas.
Purpose of the Study:
- To investigate VHL gene mutations in KBrO3-induced rat renal tumors.
- To assess the relevance of these rat tumors for human health risk assessment.
Main Methods:
- Microscopic examination of rat renal tumors.
- DNA extraction and analysis of the VHL gene (coding and promoter regions).
- Polymerase chain reaction-single strand conformation polymorphism and DNA sequencing.
Main Results:
- Two of nine clear cell renal tumors had C to T mutations in the VHL promoter's Sp1 binding motif.
- One untreated rat had a VHL promoter mutation outside the conserved core region.
- VHL coding sequence mutations were rare, and absent in chromophilic tumors.
Conclusions:
- KBrO3-induced rat renal tumors are morphologically similar to human tumors.
- The genetic mechanisms of tumorigenesis differ between rat and human clear cell renal tumors.
- VHL promoter mutations may play a role in KBrO3-induced rat renal carcinogenesis.