Global metabolomics profiling, dietary factors, and colorectal cancer risk in the NIH-Consortium of Metabolomics Studies (COMETS)

NIH 代谢组学研究联盟 (COMETS) 中的全球代谢组学分析、饮食因素和结直肠癌风险

• 批准号: 10645028
• 负责人: Mary Christine Playdon
• 金额: $ 7.47万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-14 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645028
• 关键词: Address; Age; Alcohols; Asia; Biological Assay; Biological Markers; Biology; Blood; Blood specimen; Body mass index; Cancer Etiology; Chemicals; Clinical; Clinical Data; Collection; Colon; Colorectal Cancer; Consumption; Data; Data Set; Diagnosis; Diagnostic; Diet; Dietary Assessment; Dietary Factors; Dietary Fiber; Dietary intake; Disease; Ensure; Environment; Etiology; Europe; Female; Fishes; Food; Frequencies; Funding; Future; Goals; Heterogeneity; In Vitro; Incidence; Investigation; Laboratories; Link; Lipids; Location; Logistic Regressions; Malignant Neoplasms; Measurement; Mediating; Mediation; Metabolic; Metabolic Pathway; Metadata; Methods; Modeling; Names; Nested Case-Control Study; Nutritional; Obesity; Pathway interactions; Patient Self-Report; Physical activity; Play; Population; Population Heterogeneity; Preparation; Prevalence; Processed Meats; Prospective Studies; Prospective cohort; Prospective, cohort study; Public Health; Publishing; Questionnaires; Rectum; Research; Risk; Risk Factors; Role; Sex Differences; Site; Smoking; Standardization; Statistical Data Interpretation; Subgroup; Testing; Time; United States; United States National Institutes of Health; United States Preventative Services Task Force; Validation; Vegetables; Work; anticancer research; aqueous; biomarker identification; blood-based biomarker; cancer biomarkers; cancer diagnosis; case control; clinical application; cohort; colorectal cancer prevention; colorectal cancer risk; data integration; design; diet and cancer; dietary; epidemiologic data; experience; improved; in vivo; innovation; lifestyle factors; liquid chromatography mass spectrometry; male; metabolomics; novel; novel marker; prospective; rectal; risk prediction; screening; sex; stem; study population; tumor

Summary The prevalence of colorectal cancer (CRC) continues to increase worldwide and it remains the third most commonly diagnosed cancer in the United States. An enhanced understanding of CRC etiology is essential to develop tailored risk prediction methods. Metabolomics, the comprehensive study of small metabolites, is a promising approach to discover etiological biomarkers for CRC. Metabolomics analysis in combination with information on dietary intake could be used for the identification of objective dietary biomarkers for CRC. However, precise metabolic biomarkers to predict CRC are missing. To date, there are no objective dietary biomarkers for CRC risk and the biology underlying the relationship between diet and CRC remains poorly understood. The goal of the proposed work is to investigate associations of metabolites with CRC risk and to enhance our understanding of the underlying biology of the diet-CRC relationship. To achieve this goal, we will use existing global metabolomics data generated in three state-of-the art laboratories using pre-diagnosis biospecimens from eight independent, prospective cohorts from the US, Europe, and Asia. These well- annotated and unique datasets include data from n=3,085 matched case-control pairs from diverse populations, and thus ensure broad generalizability and clinical applicability of identified biomarkers. Data are integrated in the NIH-funded Consortium of Metabolomics Studies (COMETS) together with standardized and validated food frequency questionnaires (FFQ), and epidemiologic and clinical data. We will discover and validate novel blood-based metabolic biomarkers for CRC risk (Aim 1) in a discovery set of n=1,900 matched case-control pairs. Findings will be confirmed in an independent validation set including n=1,185 matched case-control pairs. Additionally, we will perform stratified analyses by sex, tumor location, and age at diagnosis to advance our understanding of CRC etiology across distinct subtypes. Using the described datasets, we will discover and validate correlations of food groups with metabolites. We will perform mediation analysis for the top performing diet-metabolite correlations to investigate the indirect effect of diet on CRC risk through metabolites (Aim 2). The proposed research is highly innovative in that it uses a rigorous multi-step design, employs for the first time a broad set of metabolic biomarkers (n~381) and dietary information, from highly characterized cohorts with biospecimens and questionnaires collected before cancer diagnosis, thus, protecting against reverse causation. Our interdisciplinary team has extensive experience in using metabolomics in cancer research and leverages substantial preliminary data. We expect that our investigation will discover and validate novel CRC biomarkers and enhance our understanding of the underlying biology of diet in CRC etiology, thus addressing a clearly defined clinical and public health need.

概括 结直肠癌 (CRC) 的患病率在全球范围内持续增加，仍然是第三大癌症 在美国常被诊断为癌症。加深对 CRC 病因学的了解至关重要 开发量身定制的风险预测方法。代谢组学是小代谢物的综合研究 发现 CRC 病因生物标志物的有希望的方法。结合代谢组学分析 膳食摄入信息可用于识别结直肠癌的客观膳食生物标志物。 然而，缺乏预测结直肠癌的精确代谢生物标志物。迄今为止，尚无客观的饮食 结直肠癌风险的生物标志物以及饮食与结直肠癌之间关系的生物学基础仍然很差 明白了。 拟议工作的目标是调查代谢物与 CRC 风险的关联并增强 我们对饮食与结直肠癌关系的基本生物学的理解。为了实现这个目标，我们将使用 三个最先进的实验室使用预诊断生成的现有全球代谢组学数据 来自美国、欧洲和亚洲的八个独立的前瞻性队列的生物样本。这些好—— 带注释的独特数据集包括来自不同来源的 n=3,085 个匹配病例对照对的数据 人群，从而确保已确定的生物标志物的广泛普遍性和临床适用性。数据是 与标准化和 经过验证的食物频率调查问卷（FFQ）以及流行病学和临床数据。我们将发现并 在 n=1,900 的发现集中验证新型血液代谢生物标志物的 CRC 风险（目标 1） 匹配的病例对照对。研究结果将在独立验证集中得到确认，其中 n=1,185 匹配的病例对照对。此外，我们将按性别、肿瘤位置和年龄进行分层分析 诊断以增进我们对不同亚型的 CRC 病因学的理解。使用所描述的 数据集，我们将发现并验证食物组与代谢物的相关性。我们将表演 对表现最佳的饮食-代谢物相关性进行中介分析，以研究间接影响 饮食通过代谢物影响 CRC 风险（目标 2）。拟议的研究具有高度创新性，因为它使用 严格的多步骤设计，首次采用了广泛的代谢生物标志物 (n~381) 和饮食 信息来自高度特征化的队列，其中包括癌症前收集的生物样本和问卷 诊断，从而防止反向因果关系。我们的跨学科团队在以下方面拥有丰富的经验 在癌症研究中使用代谢组学并利用大量初步数据。我们期望我们的 调查将发现并验证新的 CRC 生物标志物，并增强我们对 结直肠癌病因学中饮食的基础生物学，从而满足明确定义的临床和公共卫生需求。