The incidence of esophageal adenocarcinoma is among the most rapidly rising in the United States. The cancer has been associated with obesity, sedentary life style, and Western diet. Barrett's esophagus is an intestinal metaplasia of the distal esophageal mucosa that is an accepted premalignant lesion associated with esophageal adenocarcinoma. Barrett's esophagus is associated with prior symptoms of gastroesophageal reflux disease, and the association of Barrett's esophagus with obesity is likely due at least in part to a mechanical effect promoting reflux. But obesity is associated with other cancers as well, for which no mechanical explanation exists, and alterations in levels of circulating peptide adipokines have been associated with a number of cancers and pre-cancerous conditions, including Barrett's esophagus and esophageal adenocarcinoma. Peptides are just one broad type of molecule found in circulation. Hundreds of small molecule metabolites circulate in blood. The """"""""metabolome"""""""" refers to the global pattern of small molecule metabolites. The metabolome is a richly detailed phenotype that reflects an outcome of complex interactions of genetic, epigenetic, behavioral, and environmental factors. High-throughput platforms for the analysis of the metabolome (""""""""metabolomics"""""""") have recently been developed. Panels of metabolites (""""""""metabolomic profiles"""""""") might represent a particularly efficient method for stratifying risk for the obesity-related outcome of Barrett's esophagus, and may unveil new understandings of mechanisms by which obesity promotes cancer. The proposed study utilizes specimens from an ongoing inception cohort of Barrett's esophagus cases and noncases, funded by the PI's NIDDK K23 award """"""""The Epidemiology of Adipokines in Barrett's Esophagus"""""""" (K23DK079291). We propose using high-throughput technology to assay the metabolome in stored plasma, and propose a Bayesian analytic approach to handle the very rich dataset provided by metabolomics. The proposed specific aims are to: 1. Estimate the effect of specific plasma metabolomic profiles on the risk of Barrett's esophagus in adult men. 2. Estimate the mediator effect of the specific metabolomic profiles for conventional predictors of Barrett's esophagus, including obesity, dietary intake, physical activity, and tobacco use. 3. Determine whether the metabolomic profiles improve the diagnostic accuracy over conventional predictors for Barrett's esophagus. The proposed translational study will apply the promising technique of metabolomics to patient-centered research, likely resulting in identification of metabolic pathways involved in obesity's promotion of malignancy, and possibly novel strategies of risk-stratification for esophageal adenocarcinoma. The study would continue work along the PI's long-term research goal to use outcomes and translational research methods to develop cost-effective strategies for reducing mortality from esophageal adenocarcinoma.

Public Health Relevance

The incidence of esophageal adenocarcinoma is among the most rapidly rising in the United States. This study aims to identify and estimate the effect of specific metabolic profiles circulating in the blood on the risk of developing Barrett's esophagus, a premalignant lesion associated with esophageal adenocarcinoma. If so, measurement of these metabolites may be useful in a screening program.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Rubenstein, Joel H (2012) Shedding some light on the etiology of adenocarcinomas of the esophagus and gastric cardia. Am J Gastroenterol 107:1814-6
Lewis, Jason J; Rubenstein, Joel H (2011) Barrett's esophagus progressing to cancer: a needle in a haystack? Clin Gastroenterol Hepatol 9:194-5