Mutations in oncogenes and tumor suppressor genes in animal and human tumors may give important clues as to the exposures that led to the tumors, and the cellular events that translate genetic damage into abnormal phenotype. Similarly, analysis of gene products may be informative. In an analysis of mutations in the p53 tumor suppressor gene in a large series of Italian gastric cancers from a high-incidence area, we have found for the first time a notably high frequency of hot spot mutations in codons 175 and 273. Mutations at these codons have been common in cancers of lung, colon, breast, and thyroid, but have not been discovered in previous studies of gastric carcinoma. The possibility of a specific dietary or environmental exposure leading to these hot spot mutations has implications for prevention and requires further investigation. Another gene of human relevance is the von Hippel-Lindau (VHL) tumor suppressor gene, mutated in a high percentage of both familial and sporadic renal cell carcinomas. Mutations and altered expression of this gene were sought in a series of eosinophilic epithelial tumors, nephroblastomas, and renal mesenchymal tumors caused in rats by perinatal nitrosamines. Although no mutations were discovered, immunostaining revealed loss of expression in 7/10 cortical epithelial and 9/10 nephroblastomas, compared with normal renal tubule cells, suggesting that suppression of VHL protein may also contribute to renal carcinogenesis. A series of clear cell tumors, phenotypically homologous to human kidney cancers, has been obtained in collaboration with Dr. Gordon Hard; preliminary findings indicated VHL mutations in these tumors. Proteins associated with cell cycle control may function as oncogenes if overexpressed. The liver toxicant fumonisin B1, an important contaminant of corn products throughout the world, causes liver tumors in rats by a nongenotoxic mechanism. We have found by immunohistochemistry that cyclin D1 was increased in the nuclei of preneoplastic foci, adenomas and carcinomas caused in rat liver by fumonisin B1, changes confirmed by Western immunoblotting of acutely- exposed rats. Similar changes were not noted in rat liver tumors caused by nitroglycerin or nitrosamine initiation-phenobarbital promotion, suggesting a specific effect of the mycotoxin.
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