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.
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