Metabolome Risk Factors for Barrett's Esophagus

描述(申请人提供)：食管腺癌的发病率是美国上升最快的疾病之一。癌症与肥胖、久坐不动的生活方式和西方饮食有关。Barrett‘s食道是食管远端粘膜的肠化生，是公认的与食管腺癌相关的癌前病变。Barrett‘s食道与胃食道反流病的既往症状有关，Barrett’s食道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，目前还没有机制解释，循环肽脂肪因子水平的变化与许多癌症和癌前疾病有关，包括巴雷特氏食道癌和食管腺癌。多肽只是在循环中发现的一种广泛类型的分子。数以百计的小分子代谢物在血液中循环。“代谢组”指的是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。新近开发了用于代谢组分析的高通量平台(“代谢组学”)。代谢物面板(“代谢物图谱”)可能代表了一种特别有效的方法来分层巴雷特食道肥胖相关结果的风险，并可能揭示肥胖促进癌症的机制的新理解。这项拟议的研究利用了正在进行的Barrett‘s食道病例和非病例的初始队列的样本，由PI的NIDDK K23奖“Barrett’s食道中脂肪因子的流行病学”(K23DK079291)资助。我们建议使用高通量技术来检测储存的血浆中的代谢组，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。拟议的具体目标是： 1.评估特定的血浆代谢谱对成年男性Barrett‘s食道风险的影响。 2.评估特定代谢特征对Barrett‘s食道传统预测因素的中介作用，包括肥胖、饮食摄入量、体力活动和吸烟。 3.确定与传统的Barrett‘s食道预测指标相比，代谢组学指标是否提高了诊断的准确性。 这项拟议的转译研究将把前景看好的代谢组学技术应用到以患者为中心的研究中，可能导致识别肥胖促进恶性肿瘤的代谢途径，并可能为食管腺癌的风险分层提供新的策略。这项研究将继续沿着PI的长期研究目标开展工作，使用结果和翻译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：食管腺癌的发病率是美国上升最快的疾病之一。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‘s食道的风险的影响，Barrett’s食道是一种与食管腺癌相关的癌前病变。如果是这样的话，对这些代谢物的测量在筛查计划中可能是有用的。

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.