INDUCTION OF DIFFERENT GENETIC CHANGES BY DIFFERENT CLASSES OF CHEMICAL CARCINOGENS DURING PROGRESSION OF MOUSE SKIN TUMORS

By analysis of skin tumors from F-1 hybrid mice we demonstrated that t he genetic events that occur during tumor progression depend on the ty pe of chemical carcinogenesis protocol used to induce tumor growth. Mo re than 95% of tumors induced by initiation with 7,12-dimethylbenz[a]a nthracene (DMBA) and promotion with 12-O-tetradecanoyl-phorbol-13-acet ate (TPA) exhibited mutations in Ha-ras and trisomy of chromosome 7. C arcinomas induced with multiple DMBA treatments had a lower frequency of alterations on chromosome 7 (50%), but only in tumors with Ha-ras m utations, and had a much wider spectrum of alterations, including tris omy, mitotic recombination, deletion, and gene duplication. Carcinomas induced with multiple N-methyl-N'-nitro-N-nitrosoguanidine treatments only rarely exhibited alterations on chromosome 7 (8%), even if they contained mutant Ha-ras. More frequent numerical alterations of chromo some 1 1 were also seen in TPA-promoted tumors (23%) than in tumors in duced by multiple carcinogen treatments (8%). These results show that postinitiation events are nonrandom and fit a model in which promoting agents induce numerical chromosomal alterations but in which mutagens cause more directed mutational events. (C) 1994 Wiley-Liss, Inc.