Involvement of ras oncogenes in the initiation of carcinogen-induced tumors.

More than fifteen different oncogenes have already been identified in human tumors to date. Some of these oncogenes, in particular those of the ras gene family, have been found to be reproducibly activated in a variety of carcinogen-induced animal tumor systems. In rats, almost 90% of the mammary carcinomas induced by a single dose of nitroso-methylurea (NMU) possess H-ras-1 oncogenes. We have shown that each of these oncogenes becomes activated by G----A transitions, the type of mutation most frequently induced by NMU. No such mutations have been observed when similar tumors were induced by dimethylbenz(a)anthracene (DMBA), a carcinogen of undefined mutagenic specificity. These results strongly suggest that H-ras-1 oncogenes are activated by NMU during initiation of carcinogenesis. These findings represent the first identification of a cellular locus relevant to neoplasia as a target for the mutagenic properties of a chemical carcinogen.