A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice

Abstract

Pulmonary adenoma susceptibility 1 (Pas1) is the major mouse lung cancer susceptibility locus on chromosome 6 (ref. 1), spanning a region containing six genes 2 , one of which is Kras2. Kras2 is a common target of somatic mutation in chemically induced mouse lung tumors 3,4 , and is a candidate Pas1 gene 5 . M. spretus mice (SPRET) carry a Pas1 resistance haplotype for chemically induced lung tumors 6 . We demonstrate here that the SPRET/Ei Pas1 allele is switched from resistance to susceptibility by fixation of the parental origin of the mutant Kras2 allele in Kras2 LA2 mice. This switch correlates with low expression of endogenous Kras2 in SPRET/Ei. We propose that the Pas1 modifier effect is due to Kras2, and that a sensitive balance between the expression levels of wild-type and mutant alleles determines lung tumor susceptibility. These data demonstrate that cancer predisposition should also be considered in the context of somatic events, and could have major implications for the design of human association studies to identify cancer susceptibility genes. KeywordsLung Cancer; Pas-1; Susceptibility; Kras2The critical Pas1 interval encompasses Bcat1, Lrmp, Las1, Ghiso, Kras2,. Of these, only Kras2 is a known target of mutation in lung tumors 3,4 , and mice expressing oncogenic Kras2 have a high incidence of early onset lung cancer 7,8 . Lung tumors from F1-hybrid mice showed a strong bias for Kras2 mutation involving the allele inherited from the more susceptible parent 9 , rendering Kras2 a candidate for Pas1. However, no coding sequence differences in Kras2 have been detected among all mouse strains studied, and the possible mechanisms by which Kras2 may contribute to the effect of Pas1 remain unclear, causing some investigators to focus on other genes in the Pas1 region COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. hybrids generated between Kras2 LA2 FVB/N and SPRET/Ei had relatively low tumor incidence and number at 6 months ( Fig. 1a), and some animals survived well over one year without becoming moribund. HHS Public AccessWe mated female FVBSPRETF1 hybrids with male Kras2 LA2 FVB/N mice to generate a large population of interspecific backcross mice. A total of 224 (FVBSPRETF1)FVBKras2 LA2 backcross mice were aged to 6 months, and sacrificed for assessment of tumor number. The distribution of tumor number was very wide (Fig. 1a), in agreement with the observation that there are many lung tumor susceptibility/resistance loci 15,16 . These animals were genotyped using markers on chromosome 6 to test for linkage to Pas1. We initially envisaged two possible outcomes: (i) If Kras2 is the Pas1 gene, there should be no linkage to the region, as every mouse carries the same parental mutant allele. This would be compatible with a mechanism in which selection for a more highly active or highly expressed Kras2 mutant allele in chemical carcinogenesis studies accounts completely for the effect of Pas1 (ref. 9). (ii) IfPas1 is a different gene(s) in the regi...

The Pathology of Aging 129S6/SvEvTac Mice

“…5,18,39 Interestingly, proclivity for the development of spontaneous pulmonary tumors in the 129X1/SvJ mouse appears to be directly linked with a specific pulmonary adenoma susceptibility 1 (Pas1) haplotype that leads to constitutive overexpression of K-ras in the lung. 7,68 Thus, a similar molecular mechanism might be responsible for the high incidence of lung and Harderian gland tumors observed in other 129 substrains.…”

Rare codons capacitate Kras-driven de novo tumorigenesis

“…Loss of 1 Kras allele can substantially increase sensitivity to urethane, suggesting that the nononcogenic (WT) Kras allele suppresses the tumorigenic activity of the oncogenic Kras allele (18). As such, increasing expression of the nononcogenic Kras allele, in this case by converting rare codons into common codons, could be expected to reduce urethane carcinogenesis (19 Figure 1, D and E), were crossed with C57BL6/J-CMV-Cre or, to maintain a 129 background, with 129S/Sv-PRM-Cre transgenic mice to induce Cre-mediated recombination between loxP sites and delete the neo cassette. Successful excision of the neo cassette in the resulting offspring was identified by PCR amplification of genomic DNA, yielding the expected 504-bp product (Figure 1, D and E).…”

Oncogenic and Wild-type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling

“…Alternatively, different Ras isoforms might compete for common regulators, effectors, or proper localization. Prior studies indicate that wild-type Ras can antagonize the transforming potential of its oncogenic counterpart in a dose-dependent manner in vitro and in vivo (23)(24)(25), and show a strong selective pressure to lose expression of the corresponding wild-type allele of the oncogenic Ras isoform (35)(36)(37). Whereas these data support a tumor-suppressive role for the wild-type counterpart of the same oncogenic Ras isoform, our studies uncover a novel role for the remaining 2 wild-type Ras isoforms in antagonizing oncogenic Ras signaling.…”

“…1B and 1D; 2A and 2B ). Several studies show that wild-type Ras can antagonize the transforming potential of its oncogenic counterpart in vitro and in vivo (23)(24)(25). Thus, the relief of antagonism on oncogenic Ras may serve as one potential mechanism by which basal ERK signaling increases in cells depleted of wild-type Ras.…”