Most solid tumors, including lung cancer, are now thought to progress through a series of clinical and histopathological stages. This progression is accompanied by a series of genetic changes which include activation of protooncogenes and loss of somatic chromosomal material associated with inactivation of tumor suppressor genes. Several studies have suggested that k-ras activation and loss of alleles on chromosomes 3p, 5q, 11p, 13q, and 17p are commonly found in many lung tumors. Additionally, mutations of the p53 gene, on chromosome 17p, have been found to be the most common mutations in human tumors, including lung cancer. The studies outlined in this proposal are aimed at developing a genetic model of lung cancer progression and ultimately new screening strategies. First, the larynx will be used as a well defined histopathologic model of progression for squamous cell carcinoma (SCC) to define the order of progression for the genetic changes listed above. This will quickly be expanded to include SCC of the lung, and then other histologic lung tumor types. Second, mutations of the p53 and the k-ras genes will be documented for a variety of lung tumors, and specific mutations will be compared to common risk factors (tobacco, alcohol) and unusual carcinogens such as nickel and chromium. Third, novel screening strategies based on previously established PCR-based assays will be developed for lung cancer patients. the combination of the above studies should provide important insights into the specific genetic changes associated with lung tumor progression and how carcinogens may act to produce these changes. Additionally, the establishment of early genetic changes in lung cancer, will allow the identification of targets for new screening modalities.