H. PYLORI AND IL-1Beta IN ESOPHAGEAL ONCOGENESIS

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DESCRIPTION (provided by applicant): The reasons for the rise in esophageal adenocarcinoma in the last four decades are yet to be determined. H. pylori is the major risk factor for the development of peptic ulcer disease and gastric cancer, with the risk being higher with CagA + strains. The gastric inflammatory response to H. pylori may decrease acid production and reflux in the esophagus. Differences in the host mucosal inflammatory response to H. pylori have been attributed to IL-1beta polymorphisms. The study plan will investigate how polymorphisms in the IL-1beta locus might affect the risk for esophageal cancer development. The hypothesis is that by modulating the host inflammatory response to H. pylori and subsequent acid production, the IL-1beta-31*T allele and the functionally related IL-1RN allele decrease the risk of esophageal inflammation, metaplasia, and adenocarcinoma. To test this hypothesis, a prospective cross-sectional study of adult patients referred for ambulatory endoscopy will be performed. Demographic and clinical data will be obtained via questionnaire. Blood will be obtained from patients to measure lgG to whole cell H. pylori antigens as well as to CagA, and DNA will be extracted from isolated leukocytes for IL-1 genotyping. Biopsies will be taken from the stomach and distal esophagus, and patients will undergo 24-h pH monitoring after endoscopic evaluation to evaluate esophageal acid exposure. Biopsies will be used to culture H. pylori directly from the stomach, to identify the organism by histology, to assess the histologic status of the tissues, to measure IL-1 in the stomach and esophagus, and to measure Ki-67 and COX-2 expression in the esophagus. Specific aim #1 is to determine the effect of H. py/ori strain characteristics on gastric and esophageal mucosal IL-1beta protein expression, and on the development of the precursor lesions (inflammation, metaplasia, and dysplasia) to esophageal adenocarcinoma. Specific aim #2 is to determine the prevalence of the IL-1beta-31and IL-1RN alleles in relation to esophageal acid exposure, also in relation to H. pylori colonization. In particular, the effect of the IL-1beta-31and IL-1RN alleles on gastroesophageal junction (GEJ) cellular proliferation and cyclooxygenase-2 (COX-2) expression in patients with or without H. pylori colonization will be evaluated. Specific aim #3 is to evaluate the effect of H. pylori eradication on GEJ cellular proliferation, and on IL-1beta and COX-2 expression in relation to the IL-1beta-31 allele. From these studies, both the microbial contribution and the host genotype contribution to adenocarcinoma risk should be able to be assessed, as well as to begin to define relevant cellular pathways.