) Lung cancer, the current leading cause of cancer mortality in the United States, provides the most well- documented example of the association between human exposure to exogenous genotoxicants, chiefly from tobacco smoke, and an increased risk of malignancy, specifically lung cancer. In spite of advances in basic research and clinical management of lung cancer, together with current public education to promote cessation and abstinence from smoking, deaths from lung cancer are expected to remain high well into the twenty first century. For these reasons, new approaches for the identification of at-risk individuals and early diagnosis and treatment of lung cancer are urgently needed to reduce lung cancer mortality. Lung carcinogenesis is a multiple-step process and one or more of these steps involves the induction of mutations in key cancer-related genes ultimately leading to the transformation of a normal cell into one of malignant phenotype. Mutations in two of these genes, the K-ras oncogene and the p53 tumor suppressor gene, occur in approximately 80 percent of lung tumors and have been shown to be associated with tobacco smoke exposure. The unifying hypothesis of this proposal is that genetic alterations in these two genes, including a spectrum of point mutations induced in part by exogenous carcinogens such as those found in tobacco smoke, are involved in the multiple step process leading to the development of lung cancer and thus can be used as molecular biomarkers of lung neoplasia. Characterization of these genetic changes will contribute to the understanding of the molecular etiology of the initiation and progression of lung cancer, identify events that occur early in this process and ultimately provide molecular markers for early detection of lung cancer. Toward this end, we propose to use ultra-sensitive PCR-based methods to characterize the types and levels of mutation in K-ras and p53 genes in, 1) lung tumors, bronchoaleovlar lavage (BAL), sputum, and blood samples from lung cancer patients, and 2) in BAL, sputum, and blood samples from individuals at high risk for the development of lung cancer. This pilot study is designed to validate with respect to reliability, sensitivity and prognostic accuracy of these methods for potential application as early detection biomarkers in sputum, BAL and blood samples from populations of lifetime heavy smokers at high risk for the development of cancer. For this purpose, a large cohort of these high- risk individuals is being identified, characterized and followed as part of the activities of the Epidemiology and Statistics Core of the Lung Cancer Program, and samples suitable for this study from this population will be collected and stored by the Tissue and Serum Procurement Core of the University of Pittsburgh Cancer Center (UPC).
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| Zhu, D; Zhou, J; Keohavong, P (1997) Taq-amplified fragments appear as doublets in denaturing gradient gels. Anal Biochem 244:404-6 |
