Cis-acting genomic elements of the Pas1 locus control Kras mutability in lung tumors

The Pas1 locus is the major tumor modifier of lung tumorigenesis in mouse inbred strains. Of six genes contained in a conserved haplotype, three (Casc1, Kras and Ifltd1) have been proposed as Pas1 candidates, but mechanistic evidence is sparse. Herein, we examined urethane-induced lung tumorigenesis in a new mouse model developed by replacing the Kras gene with an Hras gene in the susceptible A/J-type Pas1 locus and crossing these mice with either C57BL/6J or A/J mice. Heterozygous mice carrying the Hras-replacement gene were more susceptible than wild-type mice to lung carcinogenesis, indicating that Hras replacement not only compensates for Kras functions, but is more active. Indeed, most lung tumors carried a Gln61Leu mutation in the Hras-replacement gene, whereas no mutations were observed in the endogenous Hras gene. Thus, the context of the Kras locus determined mutability of ras genes. In mice carrying the Hras-replacement gene, the mutation frequency affecting the wild-type Kras gene was much higher when this gene was located in the A/J type than in the C57BL/6J-type Pas1 locus (12 versus 0%, -log P=5.0). These findings identify cis-acting elements in the Pas1 locus as the functional components controlling genetic susceptibility to lung tumorigenesis by modulating mutability of the Kras gene.