Esophageal cancer is a significant health problem worldwide and in the US, it accounts for the 7th leading cause of cancer death in American men. The incidence of esophageal adenocarcinoma is increasing rapidly for unknown reasons. Tobacco smoking and gastroesophageal reflux are significant risk factors for this cancer. Our recent study has cloned numbers of tobacco carcinogen benzo[a]pyrene diol epoxide (BPDE)-binding DNA fragments and identified 8 spots of chromosomal translocations in normal esophageal epithelial cells treated with BPDE. PCR analyses demonstrated that some of these translocations are reproducible in cancer cell lines and tissue specimens. We, therefore, hypothesize that tobacco smoke plays a major role in esophageal carcinogenesis and that BPDE, a metabolite of benzo[a]pyrene, is an important tobacco carcinogen that can covalently bind to DNA and cause gene mutation, deletion, chromosomal translocation, and carcinogenesis. Therefore, identification of the genes or chromosomal translocations altered by this carcinogen is of high significance and would lead to clearer insight into the mechanisms of esophageal carcinogenesis, provide biomarkers for early detection or prognosis, and perhaps provide targets for new therapies. Thus, we proposed the following Specific Aims: 1) To identify BPDE-binding DNA fragments after exposure of normal esophageal epithelial cells to benzo[a]pyrene (BP) and BPDE, to prepare a cDNA array from these BPDE-binding DNA fragments, and to identify the differentially expressed BPDE-binding genes between normal and cancerous esophageal tissues using this DNA array; 2) to evaluate and verify those differentially expressed genes from Specific Aim 1 in tissue arrays from normal, premalignant, and malignant esophageal specimens and from esophageal cancer specimens with patient follow-up, and 3) to determine these chromosomal translocations caused by BPDE in normal, premalignant, and malignant esophageal specimens and in esophageal cancer specimens with patients' follow-up. The goal of this proposal is to evaluate BPDE-binding DNA fragments and chromosomal translocations as biomarker for early detection & prognosis of esophageal cancer. ? ?
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