Evidence for age-specific genetic relative risks in lung cancer

Recent studies of familial aggregation suggest that family history of lung cancer among first-degree relatives is associated with increased risk for e arly-onset, but not late-onset, lung cancer. To assess whether this could b e explained by variability in genetic relative risk across age, segregation analysis was performed on the Louisiana Lung Cancer Dataset. This data set consisted of 337 probands who died of lung cancer between 1976 and 1979 an d their first-degree relatives. A variation of the Cox proportional hazards model was used that allowed estimation of age- and genotype-specific incid ence rates, from which the authors obtained estimates of age-specific genet ic relative risks. The best-fitting model included an autosomal dominant lo cus (allele frequency, 0.043), with carrier-to-noncarrier relative risks th at exceeded 100 for ages less than 60 years and declined monotonically to 1 .6 by age 80. The hypothesis of proportional genetic relative risk across a ge was rejected (p = 0.009), The estimated proportion of persons with lung cancer who carry the high-risk allele exceeds 90% for cases with onset at a ge 60 years or less and decreases to approximately 10% for cases with onset at age 80 years or older. These findings support previous evidence of a ma jor susceptibility locus for lung cancer and suggest that linkage studies s hould preferentially recruit young lung cancer cases and their relatives.