Comparative analysis of ras proto-oncogene mutations in selected mammalian tumors

Point mutations within ras proto-oncogenes are frequently detected in human malignancies and in different types of experimentally induced tumors in animals. In contrast to findings in experimental animal models of carcinogenesis, little is known about the incidence of ras mutations in naturally occurring animal tumors. In the present study, we investigated whether point mutations, particularly within the mutational hot-spot codons 12, 13, and 61, occur at comparable frequencies in human malignancies and spontaneously occurring tumors in other mammalian species. Two hundred seventy-nine of the most frequent canine and feline neoplasms were analyzed for changes in mutational hot-spot regions of the N-, Ki-, and Ha-ras genes. DNA fragments from exons 1 and 2 of all three ras genes were amplified by polymerase chain reaction, and the presence of point mutations was assessed by single-strand conformation polymorphism analysis and direct sequencing of amplified products. Only one sample, a case of canine melanoma, exhibited an Ha-ras mutation. Thus, our data strongly suggested that ras mutations at the hot-spot loci are apparently very rare and do not play a major role in the pathogenesis of the spontaneously occurring canine and feline tumors investigated. These observations were in marked contrast to those in experimental rodent models of carcinogen-induced mammary and skin tumors that described a consistent association with Ha- or Ki-ras activation. The role of ras oncogene activation in related human malignancies therefore cannot be readily inferred from studies of experimental carcinogenesis in animal models.