Analysis of ras gene mutational spectra in epidermal papillomas from K6/ODC transgenic mice.

In standard mouse strains, a high proportion (more than 90%) of epidermal tumors produced by initiation with 7,12-dimethylbenz[a]anthracene and promotion with a variety of chemical agents contain an activating mutation in codon 61 (A182-->T) of the c-Ha-ras gene. We analyzed the ras mutational spectra in 69 tumors induced by DMBA in a unique transgenic model, the K6/ODC mouse. In this model, low-dose DMBA treatment is sufficient per se for tumor induction, so tumor promotion with chemical agents is not required. In contrast to previous studies in standard mouse strains, our study showed that less than 50% of epidermal tumors from K6/ODC mice contained an activating codon 61 c-Ha-ras mutation (A182-->T). This result was obtained in mice initiated either as newborns (when the transgene is not expressed) or as adults (when the transgene is fully expressed). Analysis of other codon hot-spots and other ras genes revealed the presence of three codon 12 and 20 codon 61 (A182-->T) mutations in the c-Ki-ras gene in the 36 tumors that did not have c-Ha-ras mutations. We concluded that promotion in this model, by means of constitutive ornithine decarboxylase expression, causes the clonal expansion of a population of initiated cells not promoted by chemical agents.