The overall aim of this proposal is to develop a clinically valuable model of alterations in gene expression in patients, with Barrett's esophagus (BE) and Barrett's adenocarcinomas (EA). Currently, there is no accurate means of identifying, by either conventional histopathology or genetic testing the stage of disease or likelihood of Progression to dysplasia and adenocarcinoma. These facts have resulted in the need for widespread, expensive, yet relatively inaccurate surveillance of all patients with BE. We hypothesize 1) that the development and progression of Barrett's esophagus through the stages of intestinal metaplasia (IM), low grade dysplasia (LGD), high grade dysplasia (HGD), and adenocarcinoma is associated with distinct and quantifiable differences in the expression patterns of carcinogenesis-related genes; b) that genetic profiles based on quantification of expressions of a panel of progression-involved genes can be used to identify patients who have developed, or may be at higher risk of developing, adenocarcinoma or Barrett's metaplasia with dysplasia; and that c) that these adverse changes in gene expression related to development of BE can be reversed by clinical interventions.
In specific aim 1, we will test these hypotheses by quantifying, at each stage in the Barrett's IM-LGD-HGD-adenocarcinoma sequence, expressions (mRNA levels) of genes thought to be involved in malignant progression. These include cyclooxygenase-2 (cox-2) and related genes such as angiogenic factors, retinoic acid receptors, inducible nitric oxide synthase, telomerase, and others.
In specific aim 2, we will test the ability of anti-reflux (Nissen fundoplication) surgery to reverse Cox-2 and cox-2-asociated gene expression changes associated with development of BE. Gene expression profiles will be determined in pre-and post-surgery tissue samples from the same patients. Demonstration of the ability of a clinical intervention such as surgery to normalize genetic patterns may profoundly alter the treatment of patients with BE, and potentially reduce the incidence of this highly lethal cancer.
