Despite advances in treatment, lung cancer remains a major cause of mortality in the world. The ultimate goal of this project is to identify and validate genotypic and phenotypic biomarkers which could be used to identify subjects at high risk for developing lung cancer, to serve as surrogate markers of response, and for the detection of early lung cancer. By examining multiple samples of respiratory epithelium, and their cultures, we will map the extent and degree of changes in the field (Aim 1). These studies will validate the field cancerization theory and demonstrate that studies on any part of the lung will reflect changes in other parts where tumors may eventually develop. Using several molecular and cytogenetic markers known to be frequently involved in lung cancer including chromosomes 3p, 9p 5q, and 8p and the RB and p53 genes, we will compare changes in preneoplastic lesions in persons at increased risk to those inpatients who have already developed cancer, and we will determine if lung cancer is the culmination of a multistep process whereby lesions progressively accumulate, and that individuals with the greatest accumulation are at highest risk of developing cancer (Aim 2). By examining sequential bronchial biopsies from patients at increased risk (former smokers) before and after retinoid therapy, we will determine whether chemopreventive measures will re-regulate the abnormal phenotype of the affected lung (Aim 3). We have noted that mutations in preneoplastic lung lesions are not random, but target a specific allele. We will validate these observations and prove that they are not due to clonal spread by several strategies, including X-chromosome inactivation, determining whether chromosome 9 deletions target a specific chromosome homologue, comparing the allelic loss patterns in multiple primary tumors arising in the same individuals, and by determining the parental origin of the alleles lost in tumors arising in young patients (Aim 4). We have noted that telomerase, an enzyme associated with cellular immortality, is activated in most but not all lung tumors. We will determine the preneoplastic stage at which telomerase is activated, and explore its role in pathological diagnosis, staging, and prognosis by correlating activity in tumor, mediastinal nodes and resection margins with survival, tumor type, clinical parameters and pathological findings (aim 5). We will use appropriate methods for data analysis. Our studies will be closely integrated with those of several investigators of three of the other SPORE projects, and will heavily utilize Core resources. By the project's end, we will identify and validate cytogenetic and molecular biomarkers which will be useful for early detection, risk assessment, and for monitoring chemoprevention trials. In addition, our studies will have shed considerable light on the phenomenon of allele specific mutations and they will have elucidated the biological and clinical role of telomerase in lung cancer.
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