RAS MUTATIONS IN 2-AMINO-3-METHYLIMIDAZO-[4,5-F]QUINOLINE INDUCED-TUMORS IN THE CDF1 MOUSE

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) is a very potent mutagen that is carcinogenic in rodents and nonhuman primates. IQ-induced CDF1 mouse lung and liver tumors were examined for activated Ki-ras and Ha -ras genes, respectively. Polymerase chain reaction (PCR)-amplified ta rget DNAs were analyzed for mutations of codons 12, 13, and 61 by sing le-strand conformation polymorphism (SSCP) and direct sequencing metho ds. All mutations were localized to codon 61 of the ras genes. Forty-n ine of 54 lung tumors induced by IQ possessed activating Ki-ras mutati ons, as did 20 of 26 lung tumors from the vehicle-treated animals; 80% and 75% of these mutations, respectively, were A-->T transversions of the second nucleotide redundant. One lung adenoma from the IQ-treated group contained a tandem duplication of the sequence corresponding to codons 50-57 of the Ki-ras gene (unpublished observations). In additi on, seven of 34 IQ-induced liver tumors harbored activating Ha-ras mut ations: five were C-->A (G-->T) transversions at the first nucleotide, and two were A-->T transversions at the second nucleotide of codon 61 . None of the 15 liver tumors collected from the vehicle-treated mice possessed Ha-ras mutations in codon 12, 13, or 61. These data indicate that IQ induces Ha-ras gene activation in CDF1 mouse liver tumors. Th e mechanism of lung tumor induction by IQ, however, is obscured by the high frequency of Ki-ras A-->T mutations observed in both the IQ-indu ced and spontaneous lung tumors. The different ras mutational spectra in lung and liver tumors may suggest either that two different pathway s of IQ metabolism exist in these organs or that IQ contributes to CDF 1 lung tumorigenesis by a mechanism other than its direct interaction with the Ki-ras gene. (C) 1993 Wiley-Liss, Inc.