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Comparative analysis of ras proto-oncogene mutations in selected mammalian tumors
F Watzinger1, B Mayr, R Gamerith
1Children's Cancer Research Institute, St. Anna Kinderspital, Vienna, Austria.
Abstract:
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.
Insights
Ras mutations are common in human cancers but rare in spontaneous canine and feline tumors. This suggests animal models may not accurately reflect ras oncogene roles in naturally occurring pet cancers.
Area of Science:
- Oncology
- Molecular Biology
- Veterinary Medicine
Background:
- Point mutations in ras proto-oncogenes are frequent in human malignancies and experimental animal tumors.
- The incidence of ras mutations in naturally occurring animal tumors is largely unknown.
- Ras gene mutations are critical in experimental carcinogenesis models.
Purpose of the Study:
- To investigate the frequency of ras gene mutations in hot-spot codons (12, 13, and 61) in canine and feline neoplasms.
- To compare ras mutation frequencies in spontaneous animal tumors with those in human malignancies and experimental models.
- To assess the role of ras mutations in the pathogenesis of common canine and feline tumors.
Main Methods:
- Analysis of 279 canine and feline neoplasms for mutations in N-, Ki-, and Ha-ras genes.
- Amplification of ras gene exons 1 and 2 using polymerase chain reaction.
- Detection of point mutations via single-strand conformation polymorphism analysis and direct sequencing.
Main Results:
- Only one mutation (Ha-ras) was detected in a canine melanoma sample out of 279 analyzed tumors.
- Ras mutations at hot-spot loci were found to be very rare in spontaneously occurring canine and feline tumors.
- Findings contrast sharply with high ras mutation frequencies reported in experimental rodent carcinogen-induced tumors.
Conclusions:
- Ras mutations at hot-spot loci appear to play a minimal role in the pathogenesis of the studied spontaneous canine and feline tumors.
- The relevance of ras oncogene activation in human malignancies cannot be reliably inferred from experimental animal carcinogenesis models.
- Further research is needed to understand the specific oncogenic pathways in naturally occurring pet cancers.