This EDRN CVC application is a new submission by the Vanderbilt-lngram Cancer Center and its affiliated institutions. Cancer is now the number one killer of Americans, and lung cancer is the number one cause of cancer death, causing the deaths of more people than breast, colon, and prostate cancers combined. This multidisciplinary effort of experts in biomarker research proposes to take to phase II and III validation a set of biomarkers developed at our and at other institutions to address specifically the clinical utility of molecular signatures in the assessment of the diagnosis of lung cancer and of the risk of developing lung cancer. We propose a three way approach. First we propose to put diagnostic candidate signatures to the test in carefully designed case-controls studies in existing samples prospectively collected under the same standard operating procedure. Second, we will test candidate biomarkers of lung cancer development in an observational study of selected very high risk individuals from the Nashville community performing repeated measurements of clinical, imaging (chest CT) variables as well as molecular biomarker signatures some of which obtained from bronchoscopic procedures. Our hypothesis is that increased level of the biomarkers is associated with lung cancer and that measurement of the biomarker over time is likely to provide us with an advantage over the epidemiological and imaging data to detect the disease early and therefore to diagnose patients earlier, leading to larger number of patient candidates for surgical and definitive intervention. Third, we will centralize an effort to collect and store pertinent clinical data and tissues (blood, urine, and the airways specimens) following the Office of Biorepositories and Biospecimen Research guidelines as permitted by the study design and research participant authorization. We will make these resources available to the community and to collaborators within and outside of the EDRN program.