Cell-type-specific ras mutations but no microsatellite instability in chemically induced mouse skin tumors and...

In mouse skin, both papillomas/carcinomas or fibrosarcomas can be induced by 7,12-dimethylbenz[alpha]anthracene (DMBA) depending on the mode of administration. Thus, upon DMBA painting (or transplacental exposure by i.p. injection to pregnant mothers) followed by 12-O-tetradecanoylphorbol-13-acetate applications to the skin of CD1 mice, papillomas and carcinomas appeared, whereas fibrosarcomas were induced when DMBA was s.c. injected. Molecular analysis of these tumors revealed that the majority of papillomas (17/20) and carcinomas (9/10) showed DMBA-specific mutations (A to T transversion at the 61st codon) in the Ha-ras gene. On the other hand, many fibrosarcomas (5/9) showed the same mutation only in the Ki-ras gene. When microsatellites were studied in these tumors at nine loci containing CA repeats, none of them showed an instability. In addition, when we analyzed 14 BALB/c 3T3 cell lines transformed by various carcinogens (including 3 clones induced by DMBA which have the A to T mutation in the Ki-ras gene), no changes in CA repeats were observed. These results suggest that DMBA-induced mouse tumors/transformed cells show cell-type-specific ras gene mutations, and these occur independently in the absence of microsatellite instability. While murine cells are considered to be relatively susceptible to cancer induction partially due to genomic instability, our results indicate that microsatellite instability is not induced in these cells by chemical carcinogens.