These studies identify critical target genes and alterations in these genes that may be important in chemical carcinogenesis. Mutation spectra in oncogenes (eg.- ras) and tumor suppressor genes (eg.- p53 and p16) from rodent tumors induced by certain carcinogens and from tumors of individuals exposed to environmental agents are being characterized in order to understand mechanisms of chemical carcinogenesis. In one study lung tumors from mice exposed to 2,2-bis-(bromomethyl)-1,3-propanediol (a fire retardant) are being examined for k-ras mutations and other alterations that will help define mechanisms. In another study lung tumors from patients exposed to asbestos are being examined for p53 mutations. Mutations are identified by single stranded conformation polymorphism analysis, restriction fragment length polymorphisms and direct sequencing following PCR amplification of gene fragments in DNA isolated from the tumors. In a study to identify murine lung tumor susceptibility genes that may have human homologs, our lab and others mapped a major lung tumor susceptibility locus to distal chromosome 6 in the region of k-ras, and evidence is accumulating that this susceptibility locus is k-ras. Other minor loci, which may represent modifying or enhancing genes, were mapped to chromosomes 9 and 19, and selective genotyping is being continued to map these loci more closely. In addition, sequences and activities of ras guanine nucleotide exchange factors (one of which maps to the region linked with susceptibility on chromosome 9) that may interact with activated ras are being studied to see if there are differences between resistant and susceptible strains.
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