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 the genetic events that occur during tumor progression depend on the type of chemical carcinogenesis protocol used to induce tumor growth. More than 95% of tumors induced by initiation with 7, 12‐dimethylbenz[ a ]anthracene (DMBA) and promotion with 12‐ O ‐tetradecanoyl‐phorbol‐13‐acetate (TPA) exhibited mutations in Ha‐ ras and trisomy of chromosome 7. Carcinomas induced with multiple DMBA treatments had a lower frequency of alterations on chromosome 7 (50%), but only in tumors with Ha‐ ras mutations, and had a much wider spectrum of alterations, including trisomy, 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 chromosome 11 were also seen in TPA‐promoted tumors (23%) than in tumors induced 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. ©1994 Wiley‐Liss, Inc.