These studies try to identify critical target genes and alterations in these genes which may be important in chemical carcinogenesis. Certain human tumors and chemically induced tumors in animals have a high frequency of proto-oncogene activation, particularly by point mutation of ras genes, and there is evidence for chemical specificity in the pattern of mutations detected. The specific types of oncogene- activating mutations induced by a chemical carcinogen often agree with what is expected based on the DNA adducts formed by that agent. Even for """"""""non-genotoxic"""""""" carcinogens, the pattern of ras gene mutations in tumors can give clues about the mechanism of chemically induced tumorigenesis. In one study, activation of ras genes by oxazepam, a widely prescribed tranquilizer, is being investigated in order to help understand potential carcinogenic risk of these types of compounds to humans. In another study, analyses of oncogene activation in mouse liver tumors induced by TCDD as well as in tumors initiated with vinyl carbamate and promoted with TCDD are being performed in order to better understand the mechanisms of carcinogenesis by these compounds. Also, human tumors from certain exposure groups, such as uranium miners, are being analyzed for oncogene (e.g.- ras) and tumor suppressor gene (e.g.- p53) mutations. Mutations are identified by single strand conformation polymorphism analysis, slot blot oligonucleotide hybridization, restriction fragment length polymorphism and direct sequencing following PCR amplification of ras or other gene fragments in DNA isolated from the tumors. At present, we are also conducting a large genetic study to identify murine lung tumors susceptibility genes.
