There are more persons who die from lung cancer than from breast, colon, and prostate cancer combined. The objective of the Genetic Epidemiology of Lung Cancer Consortium (GELCC) is to conduct family-based studies to identify susceptibility genes in familial lung cancer (FLC) that can lead to strategies for the prevention, control, and clinical management of the disease. To date, we have developed 92 FLC kindreds, including 52 families with complete lymphocyte and archival genotypes on whom we have published linkage findings (1). In 38 families having 4 or more first-degree relatives with lung cancer, we found a LOD score of 3.6 on chromosome 6q. Further restricting to the 23 families with 5 or more affected individuals in multiple generations led to a LOD score of 5.0. Additional analysis of the impact of smoking on risk of lung cancer suggested that any level of tobacco exposure increases risk among those with inherited lung cancer susceptibility on chromosome 6q, suggesting that these individuals should be targeted for smoking prevention and monitored by early detection procedures. This 6q linkage region has been implicated in the tumorigenic process of numerous tumor types, including lung. In the first funding period, we proposed to test the hypothesis that there are specific genotypes that greatly increase the risk of developing lung cancer. Our linkage analysis findings strongly support this hypothesis. We propose to further test this hypothesis by identifying the susceptibility gene on 6q and by searching for additional susceptibility loci. Aim 1: To utilize established research resources for lung cancer family studies to identify and develop new informative familial lung cancer (FLC) pedigrees for linkage analyses and extend families already identified by follow-up. Aim 2: To genotype informative individuals in the new FLC pedigrees with evenly spaced markers throughout the genome and, if required, denser markers to reduce the size of candidate regions identified by linkage analyses. Aim 3: To map lung cancer susceptibility gene(s) by genetic linkage analysis of the FLC pedigrees. Aim 4: To identify lung cancer susceptibility genes located in chromosomal regions identified in Aim 3. Because the low 5-year survival (15%) and resection rate (25%) of lung cancer makes it difficult to collect adequate DNA samples, only a multidisciplinary, collaborative effort to identify, accrue and genotype FLC families will be successful in characterizing the genetic basis of FLC.