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


Pulmonary adenoma susceptibility 1 (Pas1) is the major mouse lung cancer susceptibility locus on chromosome 6 (ref. 1). Kras2 is a common target of somatic mutation in chemically induced mouse lung tumors2,3 and is a candidate Pas1 gene4. M. spretus mice (SPRET/Ei) carry a Pas1 resistance haplotype for chemically induced lung tumors5. We demonstrate that the SPRET/Ei Pas1 allele is switched from resistance to susceptibility by fixation of the parental origin of the mutant Kras2 allele. 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.

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We are grateful to R. Del Rosario and B. Sails for technical assistance with mouse breeding and genotyping and to CIDR for genotyping of mice. This work was supported by National Cancer Institute grant U01CA84244 (A.B.) and a supplement to U01CA84306 (T.J.). A.B. acknowledges support from the Bruce and Davina Isackson Foundation and from the Barbara Bass Bakar Chair of Cancer Genetics.

Author information

The study was designed by M.D.T., J.P.L., J.H.M. and A.B.; phenotype assessment and genotyping were performed by M.D.T. and J.P.-L..; mutational and gene expression analyses were performed by M.D.T.; J.H. was involved in mouse breeding; statistical analysis was performed by J.-H.M.; T.J. provided the Kras2LA2 mice and was involved in study design and discussion of results; M.D.T. and A.B. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Correspondence to Allan Balmain.

Supplementary information

  1. Supplementary Fig. 1

    Kras2 expression in lungs of wild-type untreated (FVBSPRETF1)FVB mice. (PDF 21 kb)

  2. Supplementary Table 1

    Kras2 status in urethane-induced lung tumors. (PDF 8 kb)

  3. Supplementary Table 2

    Oligonucleotide sequences (PDF 6 kb)

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Figure 1: Lung tumor multiplicity.
Figure 2: Expression of the Pas1 candidate genes in normal lungs of different strains of mice.
Figure 3: Proposed model for the role of Kras2 in lung tumor susceptibility.