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 target DNAs were analyzed for mutations of codons 12, 13, and 61 by single-strand conformation polymorphism (SSCP) and direct sequencing methods. All mutations were localized to codon 61 of the ras genes. Forty-nine of 54 lung tumors induced by IQ possessed activating Ki-ras mutations, 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the IQ-treated group contained a tandem duplication of the sequence corresponding to codons 50-57 of the Ki-ras gene (unpublished observations).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 addition, seven of 34 IQ-induced liver tumors harbored activating Ha-ras mutations: 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. The mechanisms of lung tumor induction by IQ, however, is obscured by the high frequency of Ki-ras A-->T mutations observed in both the IQ-induced and spontaneous lung tumors. The different ras mutational spectra in lung and liver tumors may suggest either that two different pathways of IQ metabolism exist in these organs or that IQ contributes to CDF1 lung tumorigenesis by a mechanism other than its direct interaction with the Ki-ras gene.