The candidates long-term objective is to become an independent investigator, focusing on the use of biological markers to guide and improve the treatment of patients with gastrointestinal malignancies. In this proposal, he plans to perform a molecular analysis of survival in a large, prospectively collected cohort of patients with esophageal cancer. Under the mentorship of David Christiani, MD, the candidate will achieve the specific aims of examining the association between overall survival and the presence of specific genetic polymorphisms (GSTP1, GSTM1, GSTT1, CYP1A1, CYP3A5, p53, XRCC1 and ERCC2) in patients with esophageal cancer. In addition, he will examine the association between overall survival and the expression of molecular markers (p53, p21, COX-2, VEGF, and TS) in tissue biopsy specimens from these patients. The research design makes use of a prospective cohort of over 600 patients with esophageal cancer, collected as part of a larger project undertaken by the candidate's mentor examining esophageal cancer risk factors. The methods include the collection of blood samples and clinical data from each of the patients (with patient consent). DNA extracted from each of these blood specimens will be tested for the presence of specific genetic polymorphisms. In addition, stored paraffin-embedded tissue specimens for each of the patients will be retrieved and evaluated for the expression of specific molecular markers. The presence of specific polymorphisms and tissue markers will be correlated with overall survival, after adjustment for possible confounding variables. The project has important health relatedness: in the year 2002, there will be an estimated 13,100 new cases of esophageal cancer in the United States. Among all patients who develop esophageal cancer, 12,600 (96%) will develop metastatic disease and will ultimately die from their malignancy. Recent studies have suggested that the genetic polymorphisms being examined in this study affect the metabolism of both carcinogens and agents used as systemic chemotherapy, and therefore may significantly affect prognosis. Similarly, the expression of specific molecular markers in tumor tissue may affect biologic behavior and prognosis. A better understanding of the association between genetic polymorphisms, expression of tumor molecular markers, and prognosis may lead to better treatment strategies and improved survival rates for patients with esophageal cancer.
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