Predisposition to lung tumorigenesis.

Abstract

Mouse inbred strains with inherited predisposition and resistance to lung cancer provide an essential tool for the dissection of the genetics of this complex disease. We have previously mapped a major locus (Pulmonary adenoma susceptibility 1, Pas1) affecting inherited predisposition to lung cancer in mice on chromosome 6, near Kras2. Appropriate crosses that include susceptible mice (Pas1(s)) provide a model system for identifying loci that can modify the lung cancer predisposition phenotype caused by Pas1. Using this approach we have mapped the Pulmonary adenoma resistance 1 (Par1) locus that behaves like a modifier locus of Pas1. More recently, we mapped additional lung tumor resistance loci (Par2, and Par4), and a locus specifically involved with lung tumor progression (Papg1). The mapping of Pas1 in mice stimulated us to test the possible association of genetic markers located in the homologous human region (12p12) with risk and prognosis of lung adenocarcinomas in man. In the Italian population, we carried out an association study by genotyping lung adenocarcinoma patients and healthy controls for genetic markers located in the putative region of interest. Homozygosity of the A2 allele at a Kras2/RsaI polymorphism, and allele 2 at a VNTR polymorphism in the PTHLH gene showed borderline statistically significant associations with lung cancer risk. Furthermore, the same alleles were significantly associated with tumor prognosis. Studies on association were then performed in the Japanese and in European populations. In the Japanese population, the KRAS2/RsaI marker was significantly associated with prognosis of lung adenocarcinoma, whereas the European study did not confirm this association. Our results may provide evidence for the existence of the human PAS1 locus, suggesting that the mouse model of inherited predisposition to lung tumorigenesis is predictive of a human genetic mechanism of susceptibility to lung cancer.