Early diagnosis of lung cancer may reduce the mortality associated with it. We have demonstrated that multicolor-fluorescence in situ hybridization with chromosomal probes is more sensitive in detecting lung cancer cells than conventional cytologic studies are. We precisely defined genomic signatures in primary lung cancer and developed specific probes for these signatures. We also obtained biologic samples and corresponding epidemiologic and clinical data from patients with lung cancer under an Institutional Review Board approved protocol. We hypothesize that these signatures constitute biomarkers and that an in situ strategy with a panel of specific probes for the genomic signatures will be sufficiently sensitive and specific to detect early neoplasia of the lung. Based on the principle of in situ hybridization, taking advantage of array techniques, we propose to develop an innovative in situ array that will allow simultaneous measurement of these key tumor-specific genetic changes and that can be simply applied to easily accessible surrogate specimens. We will first evaluate the potential biomarkers by dual-color fluorescence in situ hybridization with lung tissue microarrays to identify a set of probes that provide the greatest overall sensitivity and specificity for detection of lung cancer cells. We will then develop an in situ genomic DNA array: a glass coverslip to which a cocktail of these probes, labeled with multicolor fluorochromes, will be bound. We will test the assay with sputum and oral brushings and lung tumor tissue specimens from consecutive patients with lung cancer who had undergone thoracotomy and compare these data with clinical covariates to determine the assay's diagnostic ability with surrogate tissues. Finally, we will combine the assay with an automated dot-counting system to develop a reliable, cost-effective, rapid genetic test for lung carcinogenesis. This study should result in the first in situ-based assay consisting of multiple specific genetic probes that can be employed for routine diagnosis with surrogate materials. This novel strategy will have substantial implications for large-scale population-based molecular epidemiologic studies and therapeutic interventions. It will also have great application for the diagnosis and staging of other types of cancer when combined with other appropriate tumor-specific genes. This project will be multidisciplinary, incorporating epidemiology, molecular biology, cytogenetics, pathology, bioinformatics, and statistics. ? ? ?
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