KI-RAS GENE-MUTATIONS AND ABSENCE OF P53 GENE-MUTATIONS IN SPONTANEOUS AND URETHANE-INDUCED EARLY LUNG LESIONS IN CBA J MICE/

Ki-ras and p53 genes are involved in human lung carcinogenesis; howeve r, the role of these genes in experimental lung tumors is not well kno wn. In our study, the CBA/J mouse strain was used to investigate the p resence of Ki-ras and p53 alterations in lung carcinogenesis of sponta neous tumors and tumors induced with high and low doses of urethane (e thyl carbamate). To study the presence of these a Iterations in the ea rly stages of lung carcinogenesis and in very small lung tumors, restr iction fragment length polymorphism and single-strand conformation pol ymorphism analyses were performed on polymerase chain reaction-amplifi ed DNA from microdissected tumoral and normal lung samples. Ki-ras gen e mutations in codons 12 and 61 were detected in all types of lung les ions, even in small and preneoplastic lesions, and their incidence inc reased with progression from lung hyperplasias (18%) to adenomas (75%) and to carcinomas (80%). Urethane exposure, in both high and low dose s, increased the incidence of Ki-ras mutations in lung tumors, especia lly in adenomas. The presence of Ki-ras gene mutations in very small u rethane-induced lung tumors and the absence of hyperplasias among the treated-group lesions may indicate that urethane accelerates tumoral p rogression. No p53 mutations were detected in exons 5-8 in any of the epithelium-derived lung tumors. Only one p53 mutation in exon 5 was fo und in a spontaneous lymphoma. Therefore, p53 mutations do not seem to cooperate with Ki-ras gene mutations or represent an alternative mole cular pathway in murine carcinogenesis. (C) 1998 Wiley-Liss, Inc.