Epistasis governs the nature of Kras mutations and neoplastic growth of urethane-induced mouse lung tumors in chromosome substitution strains (CSS).

Abstract

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CSS or consomic mice provide a novel opportunity to examine gene interactions that affect neoplastic development. The B6.A series of 20 CSS strains have a C57BL/6 (B6) background bearing a single A/J chromosome pair (e.g. B6.A6 mice are B6 mice with A/J chromosome 6). The parental B6 strain is resistant to carcinogen-induced lung tumor formation while A/J mice are vulnerable. Lung tumors were induced in 11 B6.A strains as well as A/J and B6 mice. Sixteen wks later these tumors were counted, sized, and their Kras codon 61 mutational status determined. B6.A6, B6.A11, and B6.A17 mice developed significantly more lung tumors than did B6 mice. Susceptibility loci on chromosomes 6 and 17 had previously been detected by QTL mapping of B6 and A/J mice, but the locus on chromosome 11 is novel. B6.A6 mice contain the susceptible A/J Pas1 locus previously shown to account for >60% of the difference in urethane-induced lung tumor susceptibility between A/J and B6 mice. However, this CSS strain developed only 1.8 tumors/mouse compared to 30 tumors/mouse in similarly treated A/J mice. In addition, B6.A6 lung tumors grew more slowly and were more highly differentiated than A/J tumors. This indicates that B6 alleles on other chromosomes partially inhibited full phenotypic expression of the A/J Pas1 allele. The Pas1 locus contains the protoncogene Kras, whose activating mutation is thought to be the initiating event for mouse lung tumors. Urethane treatment induces codon 61 mutations in Kras. In B6 and B6.A mice, predominantly Gln to Arg mutations occurred in Kras codon 61, while A/J mice exhibited Gln to Leu mutations at this site. Thus, sites distant from the Kras structural gene modulate the Kras mutational status of mouse lung tumors. Pas1 contains at least 3 genes that contribute to lung tumor susceptibility and growth, in addition to Kras. B6 alleles on chromosomes other than chromosome 6 interact with Pas1 to regulate lung tumor multiplicity and progression, and this modulation may be mediated in part by the particular Kras mutation contained in the clonally expanded cells. (Supported by CA33497 and CA96133.)