Metabolomic Strategies for Discovery and Validation of Biomarkers of Colorectal Cancer Recurrence

摘要 临床决策将越来越依赖于经过验证的高质量生物标记物，这些标记物可以用于 指导癌症监测，量身定做适当治疗。确定结直肠癌(CRC)标志物是 尤其重要的是，结直肠癌在男性和女性中都很常见(占美国所有癌症发病率的8%)，而且 经常致死(美国5年存活率：65%)。到目前为止，临床上有用的预测复发的生物标志物 否则，结直肠癌患者的存活率是有限的。治疗决策在很大程度上取决于临床和病理。 参数，几乎没有其他方法来指导患者的风险和治疗分层。 这项研究将集中于代谢生物标记物的发现和验证，使用1840名患者(I-III期) 根据现有ColoCare研究的6,004个重复血液样本，一个新的多中心前瞻性队列 确诊的结直肠癌患者，包括详细的人口统计学、临床、流行病学和随访数据， 血液样本在多个标准化时间点采集，使用跨研究地点的相同方案。 这种多样化的人群确保了已识别的生物标记物的广泛普适性和临床适用性。CRC是 已知会影响新陈代谢，因此预计新陈代谢改变的标志物应该会产生有用的 诊断信息。我们新陈代谢生物标志物的发现将产生新的、独特的发现，也将是 与正在进行的蛋白质组、血糖和自身抗体生物标记物的单独分析协同作用 ColoCare研究患者群体。该项目的具体目标是： 使用最先进的、经过充分验证的代谢组平台来发现和验证新的生物标记物： 1.预测结直肠癌患者的复发：使用在诊断和随访时收集的样本，我们 将确定预测I/II期和III期患者复发风险的代谢物。 2.能够早期发现结直肠癌复发：使用术后定期收集的系列样本 每隔6个月、12个月和24个月，我们将确定对疾病复发监测有用的生物标志物。 代谢物生物标记物将包括2,500种脂类和水代谢物(MW&lt；1,000；有别于 蛋白质)。我们将分别为男性和女性评估已确定的标记的表现，并执行 分析以了解影响其性能的因素。 我们的长期目标是开发临床级别的生物标记物分析，对减少 通过治疗/随访决策指导与结直肠癌相关的发病率和死亡率 复发风险的表征。建议的代谢组学平台是最先进的，已经产生了 过去有潜在有用的生物标志物，但尚未用于预测结直肠癌的预后。这个 这项研究使用了严格的多步骤设计，预计将产生临床上可靠的标记，为快速 翻译。

ABSTRACT Clinical decision making will increasingly depend on validated, high-quality biomarkers that can be used to guide cancer surveillance and tailor appropriate treatment. Identifying colorectal cancer (CRC) markers is particularly critical, as CRC is common in both men and women (8% of all incident USA cancers) and is frequently lethal (USA 5-year survival rate: 65%). To date, clinically useful biomarkers predictive of recurrence or survival for CRC patients are limited. Treatment decisions are based largely on clinical and pathologic parameters, with little else to guide risk and treatment stratification of patients. This study will focus on metabolite biomarker discovery and validation utilizing 1,840 patients (stage I-III) with 6,004 repeat blood samples from the existing ColoCare Study, a multi-center prospective cohort of newly diagnosed CRC patients, including detailed demographic, clinical, epidemiologic, and follow-up data, for which blood samples are collected at multiple standardized time points, using identical protocols across study sites. This diverse population ensures broad generalizability and clinical applicability of identified biomarkers. CRC is known to affect metabolism, and thus it is anticipated that markers of altered metabolism should yield useful diagnostic information. Our discovery of metabolic biomarkers will yield novel, distinct findings, and will also be synergistic with ongoing, separate analyses of proteomic, glycomic, and autoantibody biomarkers in the ColoCare Study patient population. This project’s specific aims are: To use state-of-the art, well-validated metabolomic platforms to discover and verify novel biomarkers: 1. Predictive of recurrence among CRC patients: Using samples collected at diagnosis and follow-up, we will identify metabolites predictive of risk of recurrence in stage I/II and stage III patients. 2. Capable of early detection of CRC recurrence: Using serial samples collected at regular post-surgical intervals (6, 12, and 24 months), we will identify biomarkers useful for disease monitoring for recurrence. Metabolite biomarkers will include >2,500 lipids and aqueous metabolites (MW<1,000; distinct from proteins). We will evaluate the performance of identified markers separately for men and women and perform analyses to understand factors that affect their performance. Our long-term goal is to develop clinical-grade biomarker assays that have a significant impact on reducing morbidity and mortality associated with CRC through guidance of treatment/follow-up decision making and characterization of risk of recurrence. The proposed metabolomics platforms are state-of-the art, have yielded potentially useful biomarkers in the past, and have not yet been used in the context of CRC prognosis. The study uses a rigorous multi-step design and is expected to yield clinically robust markers ready for rapid translation.