CELL-TYPE-SPECIFIC RAS MUTATIONS BUT NO MICROSATELLITE INSTABILITY INCHEMICALLY-INDUCED MOUSE SKIN TUMORS AND TRANSFORMED 3T3 CELLS

In mouse skin, both papillomas/carcinomas or fibrosarcomas can be indu ced by 7,12-dimethylbenz[a]anthracene (DMBA) depending on the mode of administration. Thus, upon DMBA painting (or transplacental exposure b y i.p. injection to pregnant mothers) followed by 12-O-tetradecanoylph orbol-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 ma jority of papillomas (17/20) and carcinomas (9/10) showed DMBA-specifi c 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 t umors at nine loci containing CA repeats, none of them shelved an inst ability. In addition, when we analyzed 14 BALB/c 3T3 cell lines transf ormed 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 repeat s were observed. These results suggest that DMBA-induced mouse tumors/ transformed cells show cell-type-specific ras gene mutations, and thes e occur independently in the absence of microsatellite instability. Wh ile 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 chemi cal carcinogens.