This application addresses broad Challenge Area (09) Health Disparities and Specific Challenge Topic, 09-CA- 104: Basic cancer research in cancer health disparities. Title: Polymorphism and mutation spectrum in minorities with non-small cell lung cancer Lung cancer is the leading cause of cancer related deaths in the United States. Despite similar risk factors, African-Americans have higher incidence and mortality rates from lung cancer than other populations. Numerous studies have recently demonstrated that both inherited and acquired genetic lesions have a significant impact on both the risk of developing lung cancer and the outcomes and efficacy of targeted therapies. For example, the epidermal growth factor receptor (EGFR) signaling pathway is important in the development, progression, and invasion of non-small cell lung cancer. Ethnic differences in polymorphisms and acquired mutations in the EGFR and its downstream targets have been definitively proven to exist. It is well established that mutations in the tyrosine kinase domain are more frequent in Asian populations as compared to Caucasian population residing in western countries. These mutations confer better overall prognosis and predict response to the tyrosine kinase inhibitors, erlotinib and gefitinib;however, very little data is available regarding the prevalence of these mutations in the dominant U.S. racial minorities. In another important pathway, KRAS, mutations are present in 20-30% of patients with non-small cell lung cancer. Mutated KRAS is associated with poor prognosis and resistance to the monoclonal EGFR antibody, cetuximab as well as the EGFR tyrosine kinase inhibitors erlotinib and gefitinib. Notably, the prevalence of KRAS and somatic EGFR mutations in African-Americans is unknown. Recently, genome wide association studies identified a single nucleotide polymorphisms (SNP) variation in the nicotinic receptor which correlated with an increase in genetic susceptibility to non small cell lung cancer. Increased frequency of SNP variability may be one factor that contributes to the increased incidence of non-small cell lung cancer in African-Americans, but the frequency of these in this population is undefined. Thus efforts to better understand the molecular basis for disease susceptibility, incidence, progression, prognosis, and response to biologic agents among the common U.S. racial and ethnic minorities are needed. The Comprehensive Meharry/Vanderbilt-Ingram Cancer Center Research Partnership conducts research to address the disproportional cancer incidence, morbidity, and mortality in under-represented minorities. A dual institution study to review documented cases of non-small cell lung cancers in African-Americans to determine the frequency of germ line polymorphisms, somatic EGFR mutations, and KRAS mutations is proposed. The clinical significance of a SNP in the nicotinic receptor in African-Americans will be determined by comparing known lung cancer patients with age matched controls identified through the Southern Community Cohort Study. Medical records of patients diagnosed with non-small cell lung cancer will be reviewed. Gene sequencing will identify the prevalence of EGFR mutations and KRAS mutations. The frequency of these mutations will be analyzed as independent variables to determine the clinical significance when compared to known risk factors such as smoking. The goal of this study is to determine the impact of perturbations in the EGFR pathway on genetic susceptibility, disease progression, and outcome in African-Americans with nonsmall cell lung cancer. A study of this nature has never been performed. The results should provide tremendous insight into the genomic factors which influence susceptibility, pathogenesis, drug sensitivity, and survival in African-Americans with non-small cell lung cancer. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer related deaths in the United States. Numerous studies have demonstrated that both inherited and acquired genetic lesions have a significant impact on both the risk of developing lung cancer and the outcomes and efficacy of targeted therapies. The goal of this study is to determine the impact of perturbations in the EGFR pathway on genetic susceptibility, disease progression, and outcome in African-Americans with non-small cell lung cancer.