Novel Biomarkers for Cancer-Related Fatigue: Integrating Metabolomics, Genomics and Behaviors

项目总结 从最初的诊断到治疗再到生存，患者经常报告说疲劳是一种显著的 有问题。研究表明，高达90%的癌症患者在治疗期间会经历中度到重度的疲劳。 治疗后近30%的患者接受治疗。疲劳的病理生理学被认为是多因素和 复杂性，包括宿主易感性，促炎细胞因子的产生，昼夜节律的扰乱 睡眠/活动模式，以及神经内分泌和代谢失调。然而，到目前为止，大多数研究 研究癌症相关疲劳的生物学研究将他们的重点限制在炎症上。我们提出了一个新的 方法，易感，沉淀，和永久(3P)模型，以全面检查癌症- 与疲劳相关的病理生理学。3P模型假设：(1)基因变异使患者容易患上 疲倦，(2)癌症引起的炎症和代谢紊乱及其治疗正在加速 因素，以及(3)不良饮食、缺乏运动和睡眠干扰等行为使问题持续存在。在……里面 在目前的研究中，我们将使用代谢组学的方法，研究小分子，以检验其相对 内源性代谢和细胞因子的沉淀作用以及行为因素的永久化 疲劳病理生理学，以及易感基因变异和其他因素是如何改变这些的。这 该方法提供了一个在多组学系统水平上审问癌症相关疲劳的令人兴奋的机会。至 据我们所知，与癌症相关的疲劳从来没有在代谢组的背景下进行过研究。我们将利用 详细的临床、流行病学、客观和主观行为数据以及获得的血液样本 在诊断/手术和ColoCare研究的连续长达2年的诊断后，一个大型的， 确定和验证国际多地点预期结直肠癌(CRC)幸存者队列(n=2,379) 疲劳的预报器。ColoCare研究是唯一一项收集了如此全面的 儿童权利公约范围内的生物和行为数据。这项研究有三个目标。在目标1中，我们将研究 基因组变异和其他基线特征是癌症相关疲劳的诱因。在目标2中， 我们将检查代谢体和炎症体作为癌症相关疲劳的诱发因素。在《目标3》中， 我们将进行综合分析，以评估睡眠、体力活动、饮食及其与健康的关系 基因组、代谢组和炎症体是癌症相关疲劳的持久因素。这项研究是独一无二的 在使用3P框架时，详细的纵向评估疲劳，并使用尖端技术来 测量随着时间的推移而发生的多种经济和行为变化。结果将为风险预测提供新的途径， 预防和治疗癌症相关的疲劳。

PROJECT SUMMARY From initial diagnosis through treatment and into survivorship, patients frequently report fatigue as a significant problem. Studies suggest that up to 90% of cancer patients experience moderate to severe fatigue during treatment and nearly 30% after treatment completion. Fatigue pathophysiology is thought to be multifactorial and complex, including host susceptibility, pro-inflammatory cytokine production, disruption in circadian rhythms of sleep/activity patterns, and neuroendocrine and metabolic dysregulation. However, to date most studies examining the biology of cancer-related fatigue have limited their focus to inflammation. We propose a new approach, the Predisposing, Precipitating, and Perpetuating (3P) model, to comprehensively examine cancer- related fatigue pathophysiology. The 3P model hypothesizes that: (1) genetic variants predispose patients to fatigue, (2) inflammation and metabolic dysregulation caused by cancer and its treatment are precipitating factors, and (3) behaviors such as poor diet, physical inactivity, and sleep disruption perpetuate the problem. In the current study, we will use a metabolomics approach, the study of small molecules, to examine the relative contributions of precipitating endogenous metabolism and cytokines as well as perpetuating behavioral factors to fatigue pathophysiology, and how these are modified by predisposing genetic variants and other factors. This approach offers an exciting opportunity to interrogate cancer-related fatigue at a multi-omics systems level. To our knowledge, cancer-related fatigue has never been studied in the context of the metabolome. We will leverage detailed clinical, epidemiological, and objective and subjective behavioral data as well as blood samples obtained at diagnosis/surgery and sequentially up to 2-years post-diagnosis from the ColoCare Study, a large, international, multi-site, prospective colorectal cancer (CRC) survivor cohort (n=2,379) to determine and validate predictors of fatigue. The ColoCare study is the only large cohort study that collects such comprehensive biological and behavioral data in the context of CRC. The study has three aims. In Aim 1, we will examine genomic variation and other baseline characteristics as predisposing factors for cancer-related fatigue. In Aim 2, we will examine the metabolome and inflammasome as precipitating factors for cancer-related fatigue. In Aim 3, we will conduct an integrative analysis to evaluate sleep, physical activity, diet, and their relationships with the genome, metabolome and inflammasome as perpetuating factors for cancer-related fatigue. This study is unique in using the 3P framework, detailed longitudinal evaluation of fatigue, and use of cutting-edge technologies to measure multi-omic and behavioral changes over time. Results will provide new avenues for risk prediction, prevention, and treatment of cancer-related fatigue.