Together, lung cancer and chronic obstructive pulmonary disease (COPD) are the leading cause of death related to lung disease in the US. Accumulating data indicate that the presence of COPD increases the risk of lung cancer independent of smoking. COPD is highlighted by chronic inflammation initiated by inhaling oxidant species during tobacco combustion. The idea that chronic inflammation is a risk factor for malignancy is not new as several chronic inflammatory diseases are harbingers of cancer. These strong inferences about the links between chronic inflammation and cancer are further buttressed by recent studies linking inflammation to the tumor suppressor gene, p53 and proto-oncogene Ras. Until quite recently, conventional thinking about the genesis of solid tumors has been that the process begins in epithelial cells with somatic or germ line loss of function mutations in key tumor suppressor genes. There is strong experimental evidence to shift this paradigm demonstrating that tumor associated fibroblasts and the extracellular matrix profoundly influence tumor biology. It is therefore apparent that the stroma of the COPD lung is a highly inflammatory, fibrotic milieu;one that we hypothesize is a fertile ground for promoting and nurturing oncogenic mutations resulting from tobacco carcinogens or other exogenous or intrinsic oncogenic stresses. We propose to conduct a comprehensive genome-wide examination of COPD tissue specimens- at the level of the genome, transcriptome, genome-wide ribosome translational profile and proteome - to discover neoplastic gene expression patterns in the COPD lung that are harbingers of carcinogenesis. If successful, these results will identify biomarkers that predict those COPD patients at risk of developing lung cancer, identify therapeutic targets for chemoprevention and thus alter the course of these deadly diseases. PUBLIC HEALTH RELEVANCE: COPD and lung cancer development has levied a huge negative impact on the health of Americans. Over the past 25 years, there have been major improvements in health outcomes for cardiovascular disease, stroke and many cancers. In contrast, mortality from lung cancer and chronic obstructive pulmonary disease (COPD) has increased significantly, negatively impacting the health of our citizens. The incidence of lung cancer continues to rise, killing more Americans than any other malignancy. In addition, COPD is projected to rise to third leading cause of death within the next five years. Evidence demonstrates that the presence of COPD independently increases the risk of lung cancer, and we propose is causally linked to the development of lung cancer. Given the rising mortality from these disorders, this proposal will lead to a better understanding of the causal link of COPD to lung cancer. First, it will give us a clear phenotype of the individual with COPD that is at risk for lung cancer and thus help in pre-clinical screening for possible interventions. Second, we will increase our basic understanding of the mechanistic linkage of COPD with the development of lung cancer. Furthermore, this study promises to develop new information that can be used to enhance the prediction, diagnosis, prevention, and treatment of COPD and lung cancer. Such information may further result in technologies for molecular diagnostics, and novel chemopreventive therapies for COPD and lung cancer.