Evidence for a major gene effect in early-onset lung cancer.

Genetic segregation analyses that allowed for variable age of onset of lung cancer and smoking history were performed on 337 families, each ascertained through a lung cancer patient. Results indicated compatibility of the data with Mendelian codominant inheritance of a rare major autosomal gene that acts in concert with smoking to predispose carriers to lung cancer, by producing earlier onset of the cancer when controlling for equivalent smoking levels. Segregation at this locus could account for 69% and 47% of the cumulative incidence of lung cancer in individuals up to ages 50 and 60 respectively, but only 22% of all lung cancers in persons up to age 70. This decrease in the importance of the gene's contribution to overall lung cancer rates at later ages is most likely a reflection of an increasing proportion of noncarriers succumbing to the effects of long-term exposure to tobacco. A significant cohort effect was found, most likely due to differing smoking patterns before and after World War I, but in both cohorts the effect of a major locus could not be rejected.