Metabolome Risk Factors for Barrett's Esophagus

描述（由申请人提供）：食管癌的发病率在美国是上升最快的。这种癌症与肥胖、久坐不动的生活方式和西方饮食有关。Barrett食管是一种发生在食管远端粘膜的肠上皮化生，是一种公认的与食管腺癌相关的癌前病变。Barrett食管与胃食管反流病的既往症状相关，Barrett食管与肥胖的关联可能至少部分是由于促进反流的机械效应。但肥胖也与其他癌症有关，对此没有机械的解释，而且循环肽脂肪因子水平的改变与许多癌症和癌前状况有关，包括巴雷特食道癌和食管腺癌。多肽只是在循环中发现的一种广泛的分子。数百种小分子代谢物在血液中循环。“代谢组”是指小分子代谢物的全球模式。代谢组是一种非常详细的表型，反映了遗传、表观遗传、行为和环境因素复杂相互作用的结果。高通量的代谢组学分析平台（“代谢组学”）最近被开发出来。代谢物组（“代谢组学图谱”）可能是一种特别有效的方法，可以对肥胖相关的巴雷特食管结果进行风险分层，并可能揭示肥胖促进癌症机制的新认识。拟议的研究使用的标本来自正在进行的Barrett食管病例和非病例的初始队列，由PI的NIDDK K23奖“Barrett食管中脂肪因子的流行病学”（K23DK079291）资助。我们建议使用高通量技术分析储存血浆中的代谢组，并提出贝叶斯分析方法来处理代谢组学提供的非常丰富的数据集。建议的具体目标是：

DESCRIPTION (provided by applicant): 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.