DESCRIPTION (provided by applicant): Eighty-seven percent of lung cancers (LC) are attributed to tobacco exposure. However, only a fraction of smokers develop cancer. Genetically determined modulation of environmental exposures is an attractive possible mechanism for the variation in host susceptibility. Loss of apoptosis has been demonstrated to be an important mechanism for lung carcinogenesis. The activation of apoptosis signaling is through an intrinsic Bcl- 2 pathway and an extrinsic or TRAIL (TNF-related Apoptosis Inducing Ligand) pathway by activation of the death receptor. Although apoptosis is evolutionarily conserved, there may be interindividual variation in apoptotic capacity in general population. Polymorphic changes on genes of TRAIL pathway have been reported to be associated with modulated apoptosis. To date, there have been no studies on the role of genetic polymorphisms in the apoptotic pathway genes as predisposing factors for LC. In this application, we aim at examining polymorphisms in genes involved in the TRAIL pathway as predisposition factor for LC. The specific aims of this proposed study are: 1) To assess frequencies of SNPs in genes in the TRAIL apoptotic pathway (DR4, DR5, FADD, caspases -8, -10, -3, and -9, and BID) in 1000 cases and 1000 controls. Our working hypothesis is that adverse alleles on TRAIL pathway genes which are associated with modified apoptosis capacity may predispose individuals to increased lung cancer risk; 2) To Assess haplotypes and diplotypes as markers of susceptibility. We will implement haplotype-based analyses to identify any additional genetic factors; 3) To apply hierarchical model to refine the risk assessment and to apply novel machine- learning tools to identify any gene-environment and gene-gene interactions. Our hypothesis is that LC is a complex disease involving multiple genes in the apoptic pathway that have common, low penetrance polymorphisms, and that these polymorphisms interacting with each other and/or environmental factors. This application is designed to build upon a data and specimen repository from on ongoing funded lung-cancer case- control study in the Department of Epidemiology. Because relevant genotype data and epidemiologic profiles are available from the parent grant, this application is both time and cost effective. The goal of this study is to further our understanding of lung carcinogenesis. Polymorphic changes on TRAIL pathway may be useful risk biomarkers to identify high-risk populations.