Is There a Genetic Basis for Lung Cancer Susceptibility?

Abstract

The major risk factor for lung cancer is exposure to tobacco smoke. Exposure to radon, heavy metals used in smelting, and asbestos also greatly increase risks for lung cancer. However, only about 11% of tobacco smokers ultimately develop lung cancer, suggesting that genetic factors may influence the risk for lung cancer among those who are exposed to carcinogens. Further support for this hypothesis is provided by several epidemiological studies and also from molecular epidemiological studies. Epidemiological studies show approximately 14-fold increased risks for lung cancer among average tobacco smokers and approximately 2.5-fold increased risks attributable to a family history of lung cancer after controlling for tobacco smoke. Segregation analyses suggest that a rare autosomal dominant gene may explain susceptibility to early-onset lung cancer, but these results explain a minority of lung cancer cases, which include a familiy history. Therefore, more common genetic variants or polymorphisms are hypothesized to affect lung cancer risk. Environmental carcinogenesis resulting from tobacco smoke exposure is a complex process that can involve activation of procarcinogens that lead to adduct formation and subsequent failure of DNA repair, which should normally remove these adducts. Studies comparing DNA repair capacity among newly diagnosed lung cancer patients and age-matched controls indicate significant differences between the two groups. On culturing with bleomycin lymphocytes from lung cancer patients and age- and ethnicity-matched controls, the lymphocytes from lung cancer cases have been consistently observed to show higher levels of chromatid breaks than the control lymphocytes. A similar assay has been developed using benzo-[a]pyrene diol-epoxide (BPDE), a reactive substrate that is derived by in vitro processes from benzo[a]pyrene, a major carcinogen in tobacco smoke. Results from this assay show an even more significantly higher level of damaged chromatids in lung cancer patients than in controls. Poor DNA repair is independent of tobacco smoking status. The cellular processes involved in DNA repair of bleomycin and BPDE have not yet been fully elaborated. However, the consistency of findings with these two carcinogens indicates that DNA repair capacity influences risk for lung cancer among individuals.