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

项目摘要 从最初的诊断到治疗，再到生存，患者经常报告疲劳是一个重要的因素。 问题.研究表明，高达90%的癌症患者在治疗期间会出现中度至重度疲劳。 治疗结束后，近30%。疲劳的病理生理学被认为是多因素的， 复杂的，包括宿主易感性，促炎细胞因子的产生，昼夜节律的破坏， 睡眠/活动模式以及神经内分泌和代谢失调。然而，迄今为止， 研究癌症相关疲劳的生物学将他们的重点限制在炎症上。我们提出了一个新 方法，诱发，消除和持续（3 P）模型，全面检查癌症- 相关疲劳病理生理学。3 P模型假设：（1）遗传变异使患者易患 疲劳，（2）癌症及其治疗引起的炎症和代谢失调正在加速 因素，以及（3）不良饮食，缺乏运动和睡眠中断等行为使问题持续存在。在 目前的研究，我们将使用代谢组学的方法，小分子的研究，以检查相对 促发内源性代谢和细胞因子以及永久性行为因素的贡献 疲劳的病理生理学，以及这些是如何通过易感基因变异和其他因素进行修改的。这 这种方法提供了一个令人兴奋的机会，在多组学系统水平上询问癌症相关的疲劳。到 据我们所知，癌症相关的疲劳从未在代谢组学的背景下进行过研究。我们将利用 获得详细的临床、流行病学、客观和主观行为数据以及血液样本 在诊断/手术时以及从ColoCare研究诊断后2年内， 国际、多中心、前瞻性结直肠癌（CRC）幸存者队列（n= 2，379），以确定和验证 疲劳的预测因素。ColoCare研究是唯一一项收集了如此全面的 CRC背景下的生物和行为数据。这项研究有三个目的。在目标1中，我们将研究 基因组变异和其他基线特征作为癌症相关疲劳的诱发因素。在目标2中， 我们将研究代谢组和炎性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，身体活动，饮食，以及它们与健康的关系。 基因组、代谢组和炎性体作为癌症相关疲劳的永久性因素。这项研究的独特 在使用3 P框架，详细的纵向疲劳评估，并使用尖端技术， 测量多组学和行为随时间的变化。研究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.