FREQUENT MUTATIONS OF KI-RAS CODON-12 IN N-BIS(2-HYDROXYPROPYL)-NITROSAMINE-INITIATED THYROID, KIDNEY AND LUNG-TUMORS IN WISTAR RATS

N-Bis(2-hydroxypropyl)nitrosamine (DHPN) is a very potent mutagen and wide spectrum carcinogen in rodents. In the present study, we investig ated mutational activation of the Ki-ras gene in eight thyroid, five k idney (four mesenchymal and one transitional cell lesion) and two lung tumors induced with DHPN. Mutations were identified using single-stra nd conformation polymorphism, restriction fragment length polymorphism and DNA sequencing analysis. All of the 15 neoplasms could be shown t o have mutations in codon 12 (GGT --> GAT). These results suggest that Ki-ras mutations are frequent events during the development of DHPN-i nduced carcinomas in these organs. In a separate experiment, moreover, we analyzed the presence of Ki-ras mutations in various: tissues 8 we eks after DHPN treatment. One of five thyroid tissues treated with DHP N was found to have the same characteristic mutation, suggesting that it may represent an early event during carcinogen-induced tumor format ion in the thyroid.