Metabolome Risk Factors for Barrett's Esophagus

描述（由申请人提供）：食管腺癌的发病率在美国上升最快。癌症与肥胖、久坐不动的生活方式和西方饮食有关。巴雷特食管是一种远端食管粘膜的肠上皮化生，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先前症状相关，并且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作用。但肥胖也与其他癌症有关，对此没有机械解释，循环肽脂肪因子水平的改变与许多癌症和癌前状态有关，包括巴雷特食管和食管腺癌。肽只是在循环中发现的一种广泛类型的分子。数百种小分子代谢物在血液中循环。“代谢物组”是指小分子代谢物的总体模式。代谢组是一个非常详细的表型，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。最近已经开发了用于分析代谢组学（“代谢组学”）的高通量平台。代谢物组（“代谢组学谱”）可能代表了一种特别有效的方法，用于对Barrett食管肥胖相关结果的风险进行分层，并可能揭示对肥胖促进癌症机制的新理解。拟议的研究使用来自Barrett食管病例和非病例的正在进行的初始队列的标本，由PI的NIDDK K23奖“Barrett食管中脂肪因子的流行病学”（K23DK 079291）资助。我们建议使用高通量技术来测定储存血浆中的代谢组，并提出了一种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。拟议的具体目标是： 1.评估特定血浆代谢组学特征对成年男性Barrett食管风险的影响。 2.评估特定代谢组学特征对Barrett食管常规预测因子的中介效应，包括肥胖、饮食摄入、体力活动和烟草使用。 3.确定代谢组学特征是否能提高Barrett食管的诊断准确性。 拟议的转化研究将应用代谢组学的有前途的技术，以患者为中心的研究，可能导致参与肥胖的恶性肿瘤的促进代谢途径的识别，并可能为食管腺癌的风险分层的新策略。该研究将继续沿着PI的长期研究目标开展工作，以使用结局和转化研究方法来开发降低食管腺癌死亡率的成本效益策略。 公共卫生相关性：食管腺癌的发病率在美国上升最快。本研究旨在确定和评估血液中循环的特定代谢特征对发生Barrett食管风险的影响，Barrett食管是一种与食管腺癌相关的癌前病变。如果是这样，这些代谢物的测量可能是有用的筛选程序。

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.