Polygenic inheritance of predisposition to lung cancer.

Inherited predisposition to lung tumor development appears to be a complex genetic trait, in humans as well as in experimental animals. In humans, tobacco smoking represents the main risk factor for lung tumors. Familial clusterings of lung cancer cases are rare, although affected sib pairs are reported. However, several studies have reported an increased risk of lung cancer in first degree relatives of lung cancer patients, as compared with appropriate controls. Inheritence of particular alleles of genes or phenotypes for drug metabolizing enzymes are also associated with an increased lung cancer risk. In experimental models, murine inbred strains with high genetic predisposition to lung cancer are available, as well as resistant strains. A major locus affecting inherited predisposition to lung cancer in mice has been mapped on chromosome 6, near the Kras2 gene. The locus, pulmonary adenoma susceptibility 1 (Pas1) derives from the A/J strain. Additional "minor" loci have also been mapped. Dominant lung tumor resistance loci have also demonstrated in the mouse genome. Therefore, evidence for polygenic inheritance of predisposition to lung cancer is demonstrated in the mouse model, and it is strongly suggested for human lung cancer.