GENETIC ALTERATIONS AT MULTIPLE LOCI IN PRE-INVASIVE BRONCHIAL LESIONS

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Lung cancer is the leading cause of death in the United States and Western Europe. Currently, the diagnosis of lung cancer relies on the symptoms of cough, hemoptysis and production of sputum, and the conventional chest x- ray. This approach mainly results in the diagnosis of lung cancer in advanced stages of disease where at least two thirds of the patients have clinically detectable regional node or distant metastases. Therefore, this symptomatic diagnosis strategy cannot be relied upon to detect lung cancer in advanced stages of disease where at least two-thirds of the patients have clinically detectable regional node or distant metastases. Therefore, this symptomatic diagnosis strategy cannot be relied upon to detect lung cancer in its early and more curable stages. Several recent studies utilized modern techniques of sputum cytology and bronchoscopy to detect x-ray occult lung early stage tumors. We propose to explore the possibility that genetic analysis in conjunction with morphologic analysis can enhance the detection of curable stages of lung cancer compared to morphology alone. To determine the appropriate genetic assays, sets of the major histologic subtypes of lung cancer will be analysis at multiple loci previously implicated in lung carcinogenesis. Then premalignant lesions will be analyses for the combinations of the genetic alterations which were frequently detected in the tumor DNA. These results will be used to design genetic assays to analyze atypical cells in sputa and bronchoscopy specimens. These genetic analyses will be done in collaboration with other investigators in the Colorado SPORE as well as with investigators int he Johns Hopkins SPORE. We have begun to analyze a set of forty-four squamous cell tumors for the various genetic alterations. Analysis of chromosome 9 and 19 microsatellite markers showed LOH in 22 of the 23 tumors analyzed to date. We have also detected a homozygous deletion in 14 of the 23 tumors. Twelve of the twenty-three tumors contained a homozygous deletion at D9S126 and ten of the twenty-three contained a homozygous deletion at D9S165/263. Discrete homozygous deletions at D9S126 and D9S165/263 have not been previously reported in lung tumors. We have begun to microdissect preneoplastic lesions from these same tumors and to date have detected LOH on chromosome 9 in 2 of 5 hyperplasias, 3 of 4 moderate dysplasias, and 2 of 2 carcinoma in situ lesions. The hypothesis to be tested in this proposal is that improved methods of detection of preneoplastic changes in respiratory mucosa will result in earlier intervention and improved survival in lung cancer patients. The goals are to analyze the combination of genetic alterations and temporal sequence of events that occur in the development of human lung tumors, to determine the association between the mutational events and cellular atypia, and to further evaluate the clinical significance of atypical cells and mutations in sputa and bronchoscopic specimens. It is not cost effective to perform bronchoscopy on all high risk patients whose sputa are diagnosed as moderate/marked dysplasia; however, the approximate 5% of these patients with moderate/marked sputa diagnosis who already have a tumor would benefit by immediate detection and localization by bronchoscopy and subsequent treatment.