The overall goal of this proposal is to expand the understanding of the patterns and implications of chromosome alterations in human lung cancer and mesothelioma. Karyologic investigations will be performed on a series of tumors from patients with lung cancer or mesothelioma, with emphasis on analyses of untreated primary tumors. In order to generate meaningful correlative data, this project proposes a multidisciplinary study involving experienced collaborative investigators in the areas of cell culture cytogenetics pathology and medical oncology. The cancer cytogeneticists and cell culture experts will work closely in order to foster, improvements in existing methodologies. Several cell culture methods (growth in conventional and tumor-type specific media, and use of extra cellular matrix) will be compared in order to identify the most appropriate method(s) for successful in vitro growth of lung tumors and mesotheliomas and to determine whether different assays select for phenotypically and cytogenetically different cell populations within a tumor. This project will also evaluate and improve methods for the short-term culture and cytogenetic harvesting of cells derived from these tumors in an effort to increase the success rate and quality of karyologic investigations, including more precise identification of rearrangements and breakpoints. The karyology of both short-and long-term cultures will be assessed to determine the extent of karyotypic evolution occurring in vitro. Using the most appropriate techniques for growth and cytogenetic harvesting, we will determine the pattern of cytogenetic changes in a series of tumors to greatly expand the data base which will be required to identify recurring chromosome abnormalities. These may have biological and clinical significance. These alterations will be correlated with tumor phenotype, stage, and subsequent behavior. The proposed studies will also establish the frequency and specificity of deletions of 3p in tumors from patients with small- cell lung carcinoma. Tumors positive for double minutes and homogeneously staining regions will be examined for amplication of known or previously uncharacterized oncogenes. A long-term objective of this proposal is to relate specific chromosome defects found in lung cancer and mesothelioma to changes in the function and regulation of genes at affected breakpoints. Cells stored during this project period will be important for these future biological studies (e.g., for isolation, identification, and expression of DNA sequences that may have a significant role in tumorigenesis). Another long-term objective is to find reliable diagnostic and prognostic indicators. As the data base increases in the future, it will be possible to recognize significant correlations between the karyotype and important clinical parameters, including response to therapy.
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