Comparative analysis of ras proto-oncogene mutations in selected mammaliantumors

Point mutations within ras proto-oncogenes are frequently detected in human malignancies and in different types of experimentally induced tumors in an imals. In contrast to findings in experimental animal models of carcinogene sis, little is known about the incidence of ras mutations in naturally occu rring animal tumors. In the present study, we investigated whether point mu tations, particularly within the mutational her-spot codons 12, 13, and 61, occur at comparable frequencies in human malignancies and spontaneously oc curring tumors in other mammalian species. Two hundred seventy-nine of the most frequent canine and feline neoplasms were analyzed for changes in muta tional hot-spot regions of the N-, Ki-, and Ha-ras genes. DNA fragments fro m exons 1 and 2 of all three ras genes were amplified by polymerase chain r eaction, and the presence of point mutations was assessed by single-strand conformation polymorphism analysis and direct sequencing of amplified produ cts. Only one sample, a case of canine melanoma, exhibited an Ha-ras mutati on. Thus, our data strongly suggested that ras mutations at the hot-spot lo ci are apparently very rare and do not play a major role in the pathogenesi s of the spontaneously occurring canine and feline tumors investigated. The se observations were in marked contrast to those in experimental rodent mod els of carcinogen-induced mammary and skin tumors that described a consisre nr association with Ha- or Ki-ras arrivarion. The role of ras oncogene acti vation in related human malignancies therefore cannot be readily inferred f rom studies of experimental carcinogenesis in animal models. (C) 2000 Wiley -Liss Inc.