There has been a veritable explosion in cancer biology research highlighted by the molecular understanding of the cell cycle and its checkpoint inhibitors in controlling cell proliferation. Cancer contains 10-20 genetic lesions, and preneoplastic lesions are characterized by one or more of these. For example, in the bronchial epithelium, increasing severity of dysplasia correlates with loss of heterozygosity of tumor suppressor genes and mutations, deletions or methylation leading to gene silencing affecting key cell-cycle genes and inhibitors. Our hypothesis is that these early or preneoplastic lesions can be detected by """"""""biomarkers"""""""" that can serve as screening tools for the detection of cancer. Lung cancer, the leading cause of death due to cancer for both men and women in the United States, is characterized by 6-8 genetic lesions, usually represented by mutations of the p53 gene (50-80 percent), K-ras (50 percent of adenocarcinomas), or the INK4a locus (p16, p14ARF). Our group has shown that the metabolically activated cigarette component benzo(a)pyrene diol epoxide forms DNA adducts preferentially at guanines in codons 157, 248 and 273 of the p53 gene in bronchial epithelial cells in vitro, and these three codons are the major mutational hotspots in human lung cancers (Science 1996; 274:430-432). We propose in Aim 1 to assemble 1500 workers with greater than 30 years in construction trades and greater than 30 pack-years smoking for lung cancer screening in the NYU Institute for Cancer Treatment and Research. Tests include spiral CT scan of the chest, sputum, blood, clinical exam, questionnaires and spirometry. As a subcontract to the University of Texas, Tyler, we will screen 1000 Pantex workers exposed to ionizing radiation to gather blood, urine, medical exams, etc, to test serum antibodies to cell-cycle gene abnormalities as prospective biomarkers.
In Aim 2 we will evaluate p53 adducts in smokers' bronchial epithelium and dysplastic sites to determine if these adducts predispose to identical p53 mutations. This project will utilize DNA gene chip technology to assay many mutations simultaneously.
In Aim 3 we will utilize prospective NYU populations to evaluate Rb2 gene expression in prostate tumor samples and correlate outcome in 350 prostatectomy patients. Also, we have stored plasma from the NYU Women's Health Study, where growth factor protein levels can be measured among cancer cases and matched controls.
In Aim 4, the Ramazzini Institute will work with the machinists' union in Texas and building trades' unions in New York to enhance study subject participation in morbidity surveys. Lastly, they will develop a model on the ethical testing and use of biomarkers i the research setting.
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