Genetic mapping of a pulmonary adenoma resistance locus (Par1) in mouse

Lung cancer, a major cause of death in the Western world, has a poor prognosis1. So far, therapeutic strategies have had only a limited effect. Lung cancer risk is strongly associated with cigarette smoking2,3and lung cancer pedigrees are rare. However, a possible polygenic nature of inherited predisposition to this cancer has been envisaged4–7. Mouse inbred strains with inherited predisposition and resistance to lung cancer provide an important tool for the dissection of the genetics of this complex disease7,8. The A/J strain carries the pulmonary adenoma susceptibility 1 (Pas7) locus and develops many lung tumours9. We have mapped the M. spretus-derived locus that strongly resists the lung tumorigenesis in Pas1/+ mice. This locus, pulmonary adenoma resistance 1 (Par1) maps to mouse chromosome 11, near the Rara locus, with a lod score of 5.3. In Pas1/+ mice Par1 accounts for 23% of the phenotypic variance and 10 fold reduction in total tumour volume. These results provide evidence for a major resistance locus affecting the expression of an inherited predisposition to lung cancer.