Site‐specific Mutation of the Human c‐Ha‐ras Transgene Induced by Dimethylbenzanthracene Causes Tissue‐specific Tumors in Mice

Forestoraach squamous cell carcinomas, lung adenocarcinomas and spleen angiosarcomas were induced by dimethylbenzanthracene (DMBA) in the rasH2 transgenic mouse line carrying human c‐Ha‐ras genes with their own promoter, encoding the prototype p21 gene product. Fifteen out of 21 mice (71%) developed forestomach squamous cell carcinomas, while 15 out of 21 (71%) had lung adenocarcinomas and 3 out of 21 (14%) showed spleen angiosarcomas within 8 weeks after a single administration of 50 mg/kg DMBA intraperitoneally. Somatic mutation at the 61st codon of the transgenes, from CAG(Gln) to CTG(Len), was detected in all these newly developed tumors. However, non‐transgenic littermates demonstrated no tumors at all. These findings provide strong evidence that the somatic mutational activation of human c‐Ha‐ras genes is a critical event in tumorigenesis and a close relationship is therefore strongly suggested between the tissue‐specific development of tumors and the somatic mutation of human c‐Ha‐ras genes in these rasH2 transgenic mice.