Different susceptibility to lung tumorigenesis in mice with an identical Kras2 intron 2

The A/J mouse strain is genetically susceptible to pulmonary tumorigenesis. We have performed a genetic linkage analysis to map pulmonary adenoma susceptibility (Pas) loci in an urethane-treated (A/J x Mus spretus) x C57BL/6J (ASB) interspecific testcross. In this interspecific cross we have confirmed our previous results in AC3F2 mice on the mapping of the Pas1 locus to the distal region of chromosome 6, near Kras2 (Nature Genetics 3: 132-136, 1993). The A/J and M. spretus strains differed at the Pas1 locus, with the M. spretus providing the resistant allele. In the latter strain, we studied the nucleotide sequence of a portion of the second intron of Kras2 that contains polymorphisms associated with lung tumor susceptibility in several inbred strains. The lung tumor-resistant M. spretus strain had the same specific nucleotide sequence of susceptible strains. Mutations in codon 61 of Kras2 in urethane-induced lung tumors from ASF1 hybrids involved the A/J allele in all cases, while the M. spretus allele was never affected. Our results indicate that the M. spretus and A/J mice have an identical structure of the second intron of the Kras2 gene, but they differ in genetic susceptibility to pulmonary tumorigenesis and in mutability of their Kras2 allele.