This proposal is a joint effort among investigators with expertise in esophageal cancer and in molecular genetic investigations to identify novel genes involved in the development an/or progression of esophageal adenocarcinoma. The incidence of esophageal adenocarcinomas has increased in the United States in the last two decades. The major risk factor for the development of this disease is the presence of Barrett's metaplasia. Patients with the premalignant Barrett's mucosa have a 30-40 times greater incidence of esophageal adenocarcinoma than the general population. Analyses of the genetic alterations present in the esophageal adenocarcinomas and in the Barrett's metaplasia may provide insight into the molecular events associated with the development and progression of this disease. Moreover, identification of specific genetic alterations may provide new tools for early detection, and has the potential for developing new methods for therapeutic intervention. The applicant has implemented a novel approach for scanning the genome, based on the two-dimensional analysis of several thousand genomic restriction fragments derived from normal and tumor DNA. This technique is particularly suited for identifying regions of the DNA that contain amplified genes in tumors. Using this technique, the applicant has identified a novel genomic amplification present in a majority of esophageal adenocarcinomas analyzed.
Two specific aims are proposed: (1) to identify additional regions of genomic amplification (amplicons) in esophageal adenocarcinomas, and (2) to identify genes located in the amplicons detected in (1) and to isolate cDNAs encoded by these genes.
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