Predisposition to lung tumorigenesis

Mouse inbred strains with inherited predisposition and resistance to lung c ancer 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 susce ptible 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 tha t behaves like a modifier locus of Pas1. More recently, we mapped additiona l lung tumor resistance loci (Par2, and Par4), and a locus specifically inv olved with lung tumor progression (Papg1). The mapping of Pas1 in mice stim ulated us to test the possible association of genetic markers located in th e homologous human region (12p12) with risk and prognosis of lung adenocarc inomas in man. In the Italian population, we carried out an association stu dy by genotyping lung adenocarcinoma patients and healthy controls for gene tic markers located in the putative region of interest. Homozygosity of the A2 allele at a Kras2/RsaI polymorphism, and allele 2 at a VNTR polymorphis m in the PTHLH gene showed borderline statistically significant association s with lung cancer risk. Furthermore, the same alleles were significantly a ssociated with tumor prognosis. Studies on association were then performed in the Japanese and in European populations. In the Japanese population, th e KRAS2/RsaI marker was significantly associated with prognosis of lung ade nocarcinoma, whereas the European study did not confirm this association. O ur results may provide evidence for the existence of the human PAS1 locus, suggesting that the mouse model of inherited predisposition to lung tumorig enesis is predictive of a human genetic mechanism of susceptibility to lung cancer. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.