The incidence of adenocarcinoma of the distal esophagus and gastroesophageal junction has increased at an alarming rate of over 350% in the last few decades (1). This is among the greatest increase in incidence observed for any cancer type. When these cancers are detected early, patients have a relatively good outcome following surgical resection. The rapid vascular and lymphatic spread of this disease and the poor clinical response to radiation and chemotherapy, results in a poor outcome for most patients. Despite multimodal therapy, the 5-year survival rate for esophageal cancer remains dismal at only 5-15% (2,3). This highlights the importance of developing new methods for early cancer detection in patients with premalignant lesions such as Barrett's metaplasia and refining new treatment modalities to improve the survival of patients with this deadly disease. The presence of intestinal (Barrett's) metaplasia, a condition in which the normal squamous mucosa is replaced by columnar epithelium, is associated with esophageal adenocarcinoma (2-6). This disease is increased in obese individuals, a population rapidly expanding in the US and other Western societies. In patients with symptoms of acid reflux, Barrett's mucosa is found in ~10-12% at the time of initial endoscopy (5,6). Patients with Barrett's metaplasia have an estimated 30 to 40-fold greater risk of adenocarcinoma than the general population (3,4). The malignant potential of this condition is evidenced by the progression of non-dysplastic Barrett's metaplasia to low-grade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. For this reason, patients with known Barrett's have regular endoscopic surveillance. Currently, surveillance is performed by white light endoscopy and random four-quadrant biopsy. However, in the esophagus, precancerous lesions are flat and endoscopically Indistinct from intesinal metaplasia, thus the sensitivity and specificity of this method is limited. Moreover, this method has not been shown to reduce the rate of progression of intestinal metaplasia to adenocarcinoma (7), thus, a new strategy for surveillance of Barrett's esophagus is critically needed. Although gastroesophageal reflux disease (GERD) and the development of metaplastic changes are recognized critical events, many specific molecular events underlying adenocarcinoma development remain incompletely understood (2-6). The idea that familial factors may be involved as an autosomaldominant pattern with incomplete penetrance has been hypothesized to underlie genetic predisposition (8). The development of GERD may also reflect another aspect of familial inheritance, as it is much more frequent in both affected sibling and parent pairs when compared to spouse controls (9). The tremendous molecular heterogeneity detected in esophageal adenocarcinomas suggests multiple pathways, or specific combinations of transforming events, may be occurring in individuals with Barrett's metaplasia and that lead to adenocarcinoma. The events associated with the development of both adenocarcinoma of the lower esophagus and the gastroesophageal junction, appear to be similar and may reflect the similar efiologies. The studies proposed in this application incorporate two integrated approaches to address the increasing clinical problem of esophageal adenocarcinoma. Using our SNP-array analyses of esophageal adenocarcinoma we will first search for the repertoire of nonrandom DNA amplification that occurs in this tumor type. We will then identify the genes localized within each amplified core region and those genes that encode surface proteins. Using our gene expression database for Barrett's metaplasia without dysplasia, Barrett's with low-grade dysplasia, high-grade dysplasia and invasive adenocarcinoma we will define those genes that are specifically over-expressed in cancer cells. Tissue microarrays and immunohistochemistry will be used to validate candidate gene protein over-expression. Validated candidate genes will be transfected and over-expressed in model cell lines to allow us to select specific peptides directed against these gene products. When fluorescently-labeled, these peptides can be topically administered onto the esophagus of high-risk patients during routine endoscopy to view large surface areas and to guide tissue biopsy. In vivo validation will be performed as described in Project 2. This approach has the potential to increase patient survival by detecting cancer at a point when it is most effectively treated. We now believe we have all of the components in place to make a rational plan of attack against a growing health problem.
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