Complex segregation analysis reveals a multigene model for lung cancer.

Lung cancer risk is largely attributed to tobacco exposure, but genetic predisposition also plays an etiologic role. Several studies have investigated the involvement of genetic predisposition in lung cancer aggregation in affected families, although with inconsistent results. Some studies have provided evidence for Mendelian inheritance, whereas others have suggested that environmental models are most appropriate for lung cancer aggregation in families. To examine the genetic basis of lung cancer, we performed segregation analysis on 14,378 individuals from 1,561 lung cancer case families, allowing for the effects of smoking, sex, and age. Both a Mendelian decreasing model and a Mendelian codominant model were found to be the best fitting models for susceptibility. However, when we modeled age-of-onset, all Mendelian models and the environmental model were rejected suggesting that multiple genetic factors (possibly multiple genetic loci and interactions) contribute to the age-of-onset of lung cancer. The results provide evidence that multiple genetic factors contribute to lung cancer and may act as a guide in further studies to localize susceptibility genes in lung cancer.