Frequent codon 12 Ki-ras mutations in mouse skin tumors initiated by N-methyl-N '-nitro-N-nitrosoguanidine and promoted by mezerein

(DMBA) differ in effectiveness when tumor formation is promoted by 12-O-tet radecanoylphorbol-13-acetate (TPA). Even at high doses, MNNG is less effect ive, producing fewer benign and malignant tumors with a longer latent perio d. In DMBA-initiated skin, 10 wk of TPA promotion produced a maximal tumor response. With MNNG, 20 wk of TPA promotion was required, producing nearly four times as many papillomas as 10 wk of promotion. Promotion of MNNG-init iated skin with mezerein induced the appearance of very rapidly-growing pap illomas within 5 wk, 3 wk earlier than the first TPA-promoted papillomas. T hus, MNNG may induce a novel mutation resulting in a population of initiate d cells that respond especially well to mezerein. Since ras mutations are c ommon in experimental tumors in many tissues, we determined the frequency o f activating mutations in the Ha-ras, Ki-ras, and N-ras oncogenes. Activati ng Ha-ras mutations were present in essentially all DMBA-initiated tumor; a nd about 70% of MNNG-initiated tumors. No N-ras mutations were found in tum ors lacking other ras mutations. Surprisingly, 41% of the papillomas arisin g in the first 11 wk in MNNG-initiated, mezerein-promoted mice bore mutatio ns in codon 12 of the Ki-ras oncogene. Activating Ki-ras mutations were als o found in more than 60% of squamous cell carcinomas and 40% of keratoacant homas. Although mutations in Ha-ras are frequently detected in mouse skin t umors, mutations in Ki-ras are rare. This is the first report of mutated Ki -ras in skin tumors from mice initiated by MNNG. Published 2000 Wiley-Liss. Inc.(1)