DESCRIPTION (provided by applicant):
Helicobacter pylori (H. pylori) infection causes gastric adenocarcinoma, the second leading cause of cancer mortality worldwide. Screening and treatment of H. pylori could be a cost-effective way of preventing cancer, but whether H. pylori eradication can stop progression of gastric carcinogenesis remains unknown. Several studies have been completed that indicate incomplete regression of gastric preneoplastic conditions with H. pylori eradication. Using preneoplastic conditions as surrogate markers, however, is problematic in that regressions of surrogates may not signify regressions in cancer risk. To know the meaning of microscopic regression, one must look at the molecular underpinnings of the observed phenotypic changes.
We hypothesize that the histologic regression observed with H. pylori eradication reflects molecular changes. To determine if this is the case we will dissect the role that H. pylori plays in molecular pathways of gastric preneoplasia. cDNA microarray will be used to assess gene expression profiles of archived tissues from a randomized placebo-control trial of H. pylori eradication conducted in Mexico. A total of 90 subjects (45 from the treatment arm and 45 from the placebo arm) with preneoplastic conditions (gastritis, atrophy, and metaplasia) will be selected from the original trial. For each of the 90 subjects, a pair of pre- and post-treatment gastric tissues will be used for cDNA microarray. The resulting gene expression data will be analyzed by hierarchical clustering and Significant Analysis of Microarrays (SAM). In addition to the data on patients with preneoplastic lesions, we also have access to gene expression profiles of 90 gastric cancer tissues and 22 normal gastric tissues from investigators at our institution. Our data can then bridge the gap between different carcinogenetic stages between normal and cancer. In summary, the primary aims of this study are: 1) to assess the changes of global gene expression patterns associated with H. pylori eradication and identify reversible, molecular "intermediate biomarkers" for gastric cancer, 2) to compare the results from gene expression studies to those from pathologic diagnoses, and 3) to compare the results from gene expression studies in normal, preneoplastic, and malignant tissues.
This proposed study will not only help elucidate the poorly understood molecular mechanisms of gastric carcinogenesis, but also help delineate the role of H. pylori infection in this process. Despite National Institutes of Health (NIH) guidelines to the contrary, H. pylori screening and eradication therapy is being widely used by primary care practitioners in the hope that it will prevent cancer in high-risk populations. We hope our results will provide impetus for more rational screening and treatment policies, particularly for the minority populations in the United States and people in developing countries who suffer most from this highly fatal disease.
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