METABOLITE BIOIMARKERS IN THE DEVELOPMENT OF ESOPHAGEAL ADENOCARCINOMA

食管腺癌发生过程中的代谢生物标志物

• 批准号: 8571375
• 负责人: THOMAS L VAUGHAN
• 金额: $ 24.76万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8571375
• 关键词: Age; Amino Acids; Barrett Esophagus; Barrett' s Adenocarcinoma; Biological Assay; Biological Markers; Blood; Body mass index; Cancerous; Carbon; Caucasoid Race; Classification; Clinical; Data; Development; Discriminant Analysis; Disease; Disease Progression; Distal; Dysplasia; Early Diagnosis; Energy Metabolism; Epigenetic Process; Esophageal; Esophageal Adenocarcinoma; Foundations; Future; Gastroesophageal reflux disease; Gender; Genetic; Grant; Group Identifications; High-Risk Cancer; Incidence; Individual; International; Investigation; Laboratories; Least-Squares Analysis; Link; Lipids; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Pathway; Methods; Modeling; Molecular Weight; Monitor; Nuclear Magnetic Resonance; Nucleotides; Obesity; Pathway interactions; Patients; Performance; Population; Population Group; Population Heterogeneity; Premalignant; Proteins; ROC Curve; Receiver Operating Characteristics; Reflux; Resources; Risk; Risk Factors; Sample Size; Sampling; Sensitivity and Specificity; Serum; Smoking; Staging; Statistical Models; Stratification; Systems Biology; Testing; Urine; Validation; Work; aqueous; base; biobank; candidate marker; carcinogenesis; clinical risk; high risk; insight; lipid metabolism; male; metabolomics; novel; predictive modeling; public health relevance; research study; sex; tool; validation studies

DESCRIPTION (provided by applicant): The incidence of esophageal adenocarcinoma (EA) in the US has increased 300% over recent decades while median survival remains an abysmal 10 months. Several major risk factors have been defined for EA and its precursor, Barrett's esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, but a key challenge remains the identification of individuals at highest risk, since most with reflux do not develop BE, and most with BE do not progress to EA. While a number of genetic, epigenetic, and protein-based biomarkers have been evaluated for their ability to detect or predict disease progression, the development of novel clinical tests has been hampered by technical complexities of the required assays, limited sensitivity/specificity of the marker panels and lack of validation studies. Based on our preliminary data, we anticipate that metabolomics, the quantification of low molecular weight metabolites, offers a favorable alternative approach for identifying effective biomarkers to aid in risk stratification for those at risk of EA. Numerou studies have established that cellular energy metabolism is fundamentally altered in a broad spectrum of cancers, and increasing evidence indicates that cancer-associated metabolic changes are detectable in blood and urine. In this proposal, we hypothesize that serum-based metabolites can distinguish multiple stages of disease progression along the pathway from gastroesophageal reflux (GERD) to BE to EA. Using advanced profiling methods and a well-characterized biorepository, this collaborative proposal seeks to identify and validate novel metabolite markers linked to these disease states. In Aim 1, global metabolic profiling will be conducted on a set of 60 patient serum samples distributed across case type (GERD, BE, high- grade dysplasia/EA) to identify an expanded pool of candidate metabolite biomarkers that differ significantly across two or all of these conditions. In Aim 2, this targeted profiling of this set f metabolites plus a previously-identified panel of 28 candidates will be conducted on a larger set of 240 patient samples. Based on validated candidate markers identified, statistical models for sample classification (BE-GERD and HGD/EA-BE) will be constructed using partial least-squares discriminant analysis, and model performance estimated by Monte Carlo cross-validation. Successful completion of these aims will lay the groundwork for generating novel non-invasive tools for stratifying patients at risk of EA according to their likelihood of disease progression. Such tools have the potential to increase early detection and reduce unnecessary surveillance, by focusing intensive clinical monitoring on those at highest risk of cancer. These investigations will set the stage for larger-scale future studies, which will leverage the extensiv resources of the international Barrett's and Esophageal Adenocarcinoma (BEACON) consortium to validate our findings across population groups and identify key modifying factors that may enhance the accuracy and applicability of our predictive models.

描述（由申请人提供）：美国食管腺癌（EA）的发生率在最近几十年中增加了300％，而中位生存期仍然是糟糕的10个月。已经定义了EA及其前体Barrett食管（BE）的几个主要危险因素，包括回流，高加索人种族，男性性别，肥胖和吸烟，但是一个关键的挑战仍然是对处于最高风险的个体的识别，因为大多数与Reflux没有发展的BE，并且大多数与EA都无法发展为EA。尽管已经评估了许多遗传，表观遗传和基于蛋白质的生物标志物的检测或预测疾病进展的能力，但新型临床测试的发展受到所需测定的技术复杂性的阻碍，标记板的灵敏度/特异性有限，缺乏验证研究。根据我们的初步数据，我们预计代谢组学（低分子重量代谢物的量化）为识别有效的生物标志物提供了一种有利的替代方法，以帮助对患有EA风险的人进行风险分层。 Numerou研究已经确定，在广泛的癌症中，细胞能量代谢从根本上改变了，并且越来越多的证据表明与癌症相关的代谢变化在血液和尿液中可检测到。在此提案中，我们假设基于血清的代谢产物可以区分沿着从胃食管反流（GERD）到EA的疾病进展的多个阶段。该协作提案使用先进的分析方法和良好的生物座席，旨在识别和验证与这些疾病状态相关的新型代谢物标记。在AIM 1中，将对分布在病例类型（GERD，BE，高级发育不良/EA）的60个患者血清样品上进行全球代谢分析，以识别扩展的候选代谢物生物标志物的扩展池，这些标志物在两种或所有这些条件下都有很大差异。在AIM 2中，将在较大的240个患者样本上进行该集合F代谢物以及先前确定的28个候选面板的目标分析。基于确定的经过验证的候选标记，将使用部分最小二乘判别分析构建样品分类（BE-GERD和HGD/EA-BE）的统计模型，并由Monte Carlo交叉验证估算的模型性能。这些目标的成功完成将为生成新型的非侵入性工具奠定基础，以根据其疾病进展的可能性对患有EA的风险进行分层。这样的工具有可能通过将密集的临床监测集中在癌症风险最高的临床监测上，从而增加早期检测并减少不必要的监视。这些调查将为大规模的未来研究奠定基础，该研究将利用国际巴雷特和食管腺癌（Beacon）财团的扩展资源来验证我们跨人群群体的发现，并确定可能增强我们预测模型的准确性和适用性的关键修改因素。