ADDITIONAL EVIDENCE THAT THE K-RAS PROTOONCOGENE IS A CANDIDATE FOR THE MAJOR MOUSE PULMONARY ADENOMA SUSCEPTIBILITY (PAS-1) GENE

A locus for mouse pulmonary adenoma susceptibility, Pas-1, has been ma pped on distal chromosome 6, where the X-ras gene is located. Allele-s pecific activation and expression of the K-ras allele from the suscept ible parent has been observed in lung tumors from F1 hybrid mice. We r eport here genetic mapping of lung tumor susceptibility genes in ureth ane-treated A x B and B x A recombinant inbred (RI) mice using microsa tellite markers to seek further evidence for the K-ras gene as candida te for Pas-1. The K-ras genotype differs between the A/J and C57BL/6J Progenitors of the RI strains, and distal chromosome 6 contained a maj or lung tumor susceptibility determinant in the RI mice. Additional ev idence that Pas-1 is K-ras involved linkage analysis of (A/JOLaHsd x B ALB/ cOLaHsd) F2 intercross mice whose parents shared the same K-ras g enotype. In contrast to the results with the B x B and B x A RI strain s, no distal chromosome 6 site was significantly associated with tumor development in these F2 mice. In addition to this major locus, linkag e analysis of the RI mire revealed additional quantitative trait loci for susceptibility on chromosomes 10, 17, and 19. These loci may serve as modifiers of Pas-1. The relationship between the K-ras genotype an d the frequency of X-ras mutations in urethane-induced lung tumors fro m the RI mice was also explored. All 18 tumor NAs from RI mice with hi gh susceptibility contained an AT --> TA transversion at the second ba se of K-ras codon 61. This was also true for DNAs from 27 of 27 (100%) tumors in mice with high intermediate susceptibility. In RI strains w ith a low intermediate susceptibility, the DNA from 39 of 47 (83%) tum ors contained an AT --> TA transversion at condon 61, and only 13 of 2 1 (62%) tumors had this mutation in the most resistant group. This ref lects a positive correlation between the frequency of K-ras mutations in lung tumors of A x B or B x A RI strains and their susceptibility t o lung carcinogenesis. Since K-ras appears to be Pas-1, these results suggest that some RI mice that have the resistant K-ras or Pas-1 allel e undergo tumor development by a K-ras-independent route.