DIFFERENT SUSCEPTIBILITY TO LUNG TUMORIGENESIS IN MICE WITH AN IDENTICAL KRAS2 INTRON-2

The A/J mouse strain is genetically susceptible to pulmonary tumorigen esis. We have performed a genetic linkage analysis to map pulmonary ad enoma susceptibility (Pas) loci in an urethane-treated (A/J x Mus spre tus) x C57BL/6J (ASB) interspecific testcross. In this interspecific c ross we have confirmed our previous results in AC3F2 mice on the mappi ng 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 dif fered at the Pas1 locus, with the M. spretus providing the resistant a llele. In the latter strain, we studied the nucleotide sequence of a p ortion of the second intron of Kras2 that contains polymorphisms assoc iated with lung tumor susceptibility in several inbred strains. The lu ng tumor-resistant M. spretus strain had the same specific nucleotide sequence of susceptible strains. Mutations in codon 61 of Kras2 in ure thane-induced lung tumors from ASF1 hybrids involved the A/J allele in all cases, while the M. spretus allele was never affected. Our result s indicate that the M. spretus and A/J mice have an identical structur e of the second intron of the Kras2 gene, but they differ in genetic s usceptibility to pulmonary tumorigenesis and in mutability of their Kr as2 allele. (C) 1995 Academic Press, Inc.