Searching the blood metabolome to identify risk biomarkers for biliary tract cancer

搜索血液代谢组以确定胆道癌的风险生物标志物

• 批准号: 10453004
• 负责人: QIUYIN CAI
• 金额: $ 69.26万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453004
• 关键词: Anabolism; Asian; Asian population; Bile duct carcinoma; Biliary Tract Cancer; Biological; Biological Assay; Biological Markers; Biology; Black Populations; Blood; Blood specimen; Cancer Etiology; Cancer Patient; Cessation of life; Cholecystitis; Chronic; Data; Diabetes Mellitus; Diagnosis; Diagnostic; Dietary Practices; Etiology; Extrahepatic; Fatty acid glycerol esters; Feasibility Studies; Genetic; Genetic Risk; Hispanic Populations; Human; Incidence; Individual; Inflammation; Investigation; Maintenance; Malignant Neoplasms; Malignant neoplasm of gallbladder; Mendelian randomization; Metabolic; Metabolism; Methodology; Modeling; Morbidity - disease rate; Nature; Obesity; Pathogenesis; Patients; Pilot Projects; Play; Population; Prevention Measures; Prevention strategy; Primary Prevention; Prospective cohort study; Quantitative Trait Loci; Race; Research; Resources; Risk; Risk Assessment; Risk Factors; Role; Sample Size; Sampling; Secondary Prevention; absorption; bile duct; biliary tract; biomarker validation; cancer biomarkers; cancer diagnosis; cancer prevention; cancer risk; case control; cost effective; cost efficient; design; epidemiology study; gallstone disease; genetic variant; genome wide association study; genomic data; hepatobiliary cancer; improved; instrument; liver function; metabolome; metabolomics; mortality; multiple datasets; novel; novel marker; racial difference; risk prediction model; risk variant

Summary Biliary tract cancer (BTC), which includes cancers of the gallbladder and bile ducts, is the second most common primary hepatobiliary cancer worldwide. BTC is highly fatal, with ~90% of its patients dying within five years after diagnosis. A better understanding of the etiology of BTC is critical for designing cost-effective prevention strategies to reduce the morbidity and mortality of this fatal cancer. The biliary tract plays a central role in the metabolism and absorption of fat-soluble endogenous and exogenous compounds and in the maintenance of normal liver functions. Many known risk factors for BTC are related to metabolic disturbance, suggesting a significant role of metabolic perturbance in BTC pathogenesis. Thus, a systematic investigation of circulating metabolites could provide valuable information regarding biomarkers for BTC risk and biological mechanisms of BTC pathogenesis. Herein, we propose a well-powered, multi-ancestry study, using resources from 17 large prospective cohort studies around the world and five large genetic consortia/studies of BTC, to identify and validate metabolomic biomarkers for BTC risk. In Aim 1, we propose to analyze blood samples collected prior to any cancer diagnosis from 750 incident cases and 750 matched controls to systematically search the blood metabolome to identify promising metabolite biomarkers for replication. In Aim 2, we will use genetic variants associated with circulating metabolites and data from large genome-wide association studies (GWAS) of BTC to search for additional promising metabolite biomarkers for replication. In Aim 3, we will quantify 50 promising metabolites selected from Aims 1 and 2 and evaluate their associations with risk of BTC overall, and by its subsites, in an independent sample of nearly 2000 cases and their matched controls. Finally, in Aim 4, we will build risk prediction models for BTC using metabolite biomarkers, genetic risk variants and traditional risk factors. This is the first large study ever conducted to systematically search the blood metabolome to identify risk biomarkers for BTC, and the first study to integrate metabolomic and genomic data in BTC biomarker research. Including multi-ancestry populations will allow us to cross-validate research findings and identify potential racial differences in biomarker associations. This study will provide substantial novel data to improve the understanding of BTC etiology and identify biomarkers for BTC risk assessment.

概括 胆道癌（BTC）包括胆囊和胆管的癌症，是第二大的 全球常见的原发性肝胆癌。 BTC高度致命，约90％的患者在五个之内死亡 诊断后的几年。更好地了解BTC的病因对于设计成本效益至关重要 降低这种致命癌症的发病率和死亡率的预防策略。胆道扮演中央 在代谢和吸收脂溶性内源性和外源性化合物中的作用以及 维持正常肝功能。 BTC的许多已知危险因素与代谢紊乱有关， 表明代谢扰动在BTC发病机理中的重要作用。因此，对 循环代谢物可以提供有关BTC风险和生物学的生物标志物的有价值的信息 BTC发病机理的机制。在此，我们使用资源提出了一项功能良好的多项式研究 从世界各地的17个大型前瞻性队列研究和BTC的5个大遗传联盟/研究 确定并验证代谢组生物标志物，以实现BTC风险。在AIM 1中，我们建议分析血液样本 从750例事件病例和750个匹配的对照到系统诊断之前收集的癌症之前收集 搜索血液代谢组，以识别有希望的代谢物生物标志物以进行复制。在AIM 2中，我们将使用 与循环代谢产物和大型基因组关联研究的数据相关的遗传变异 BTC的（GWAS）寻找其他有希望的代谢物生物标志物进行复制。在AIM 3中，我们将 量化50个有前途的代谢物，从目标1和2中选择，并评估其与BTC风险的关联 总体而言，在近2000例病例及其匹配的对照的独立样本中，总体而言。最后， 在AIM 4中，我们将使用代谢物生物标志物，遗传风险变异和BTC建立风险预测模型 传统的风险因素。这是有史以来第一次进行系统地搜索血液的大型研究 代谢组以鉴定BTC的风险生物标志物，以及首次整合代谢组和基因组数据的研究 在BTC生物标志物研究中。包括多委托人的种群将使我们能够交叉验证研究 发现并确定生物标志物关联的潜在种族差异。这项研究将提供大量 新的数据以提高对BTC病因的理解并确定BTC风险评估的生物标志物。