Discovery and verification of novel biomarkers of colorectal cancer recurrence

 描述（申请人提供）：为了实现精准医学的承诺，需要更多更好的生物标志物来指导临床决策。这对于结肠直肠癌（CRC）患者尤其重要，因为：1. CRC是男性和女性中第三常见的癌症，占美国所有癌症事件的9%; 2.男性和女性中最常见的癌症，前列腺癌和乳腺癌的5年存活率分别为99%和89%，但CRC仅为64%，使其成为美国癌症相关死亡的第二大常见原因; 3.目前，缺乏临床上有用的生物标志物预测CRC患者的复发或生存，可用于指导监测和治疗。因此，存在过度治疗和治疗不足的问题，因为治疗主要基于临床和病理参数，但很少有其他风险分层患者。本研究将在新诊断的CRC患者的多中心前瞻性队列（ColoCare研究）中使用1，574名参与者。详细的人口统计学、临床、流行病学和随访数据通过沿着在多个时间点采集的血液样本确定。因此，本研究是专门设计来满足本提案的总体目标，即通过实现以下具体目标来发现和验证预测CRC患者复发的新型血液生物标志物：1.发现和验证预测CRC患者复发的新型生物标志物：利用诊断时收集的样本，我们将评估血浆蛋白质组、糖组和自身抗体库，包括评估文献中报道的有希望的标志物，使用经过充分验证的实验室方法来确定预测复发风险的标志物，以用于明确的临床应用（预测I/II期患者和III期患者的复发）。我们的发现实验中符合特定统计标准的最佳候选人将在一组与发现集中使用的患者完全分开的患者中进行评估。2.发现和验证可用于早期检测CRC复发的新型生物标志物：利用诊断后定期收集的系列样本，我们将发现可能用于使用蛋白质组学，糖组学和自身抗体平台进行疾病监测的新型生物标志物。标记物将在CEA的背景下进行评估，CEA是一种临床使用的复发生物标志物，对于检测II期和III期患者的复发性结直肠癌具有60%的灵敏度和90%的特异性。如果成功，该项目可能导致临床级生物标志物检测的发展，这可能对降低与结直肠癌相关的发病率和死亡率产生重大影响。本研究具有创新性，因为将使用的队列是独特的，高度表征的，并且具有定期收集的系列样本;将使用的独特平台已被证明可以产生潜在有用的生物标志物，并且还可以评价现有的目标标志物;并且本研究有能力鉴定具有临床意义性能特征的生物标志物。

 DESCRIPTION (provided by applicant): In order to realize the promise of precision medicine, more and better biomarkers are needed to guide clinical decision making. This is of particular importance for patients with colorectal cancer (CRC) as: 1. CRC is the third most common cancer in both men and women accounting for 9% of all incident cancers in the United States; 2. The 5-year survival rates for the most common cancers in men and women, prostate and breast cancer, are 99% and 89%, respectively, but is only 64% for CRC making it the second most common cause of cancer related death in the U.S.; 3. At present there is a lack of clinically useful biomarkers predictive of recurrence or survival for CRC patients that can be used to guide surveillance and treatment. Consequently, there are issues of both overtreatment and undertreatment because treatment is based largely on clinical and pathologic parameters, but little else to risk stratify patients. This study will utilize 1,574 participants in a multi- cente prospective cohort (the ColoCare Study) of newly diagnosed CRC patients. Detailed demographic, clinical, epidemiologic, and follow-up data are ascertained on all participants along with blood samples collected at multiple time points. Thus, this study is specifically designed to meet the overarching goal of this proposal, the discovery and verification of novel blood-based biomarkers predictive of recurrence among CRC patients, through achieving the following specific aims: 1. Discovery and verification of novel biomarkers predictive of recurrence among CRC patients: Utilizing samples collected at the time of diagnosis we will evaluate the plasma proteome, glycome, and autoantibody repertoire, including assessment of promising markers reported in the literature, using well-validated laboratory approaches to identify markers predictive of risk of recurrence for well-defined clinical applications (predictin recurrence in stage I/II patients and in stage III patients). Top candidates from our discovery experiments meeting particular statistical criteria will be evaluated in a group of patients completely separate from those used in the discovery set. 2. Discovery and verification of novel biomarkers useful for the early detection of CRC recurrence: Utilizing serial samples collected at regular intervals post-diagnosis we will discover novel biomarkers potentially useful for disease monitoring using proteomic, glycomic, and autoantibody platforms. Markers will be evaluated in the context of CEA, a clinically used biomarker of recurrence that has a 60% sensitivity and 90% specificity for detecting recurrent colorectal cancer in stage II and III patients. If successfl this project could lead to the development of clinical grade biomarker assays that could have significant impact on reducing the morbidity and mortality associated with colorectal cancer. This study is innovative in that the cohort that will be used is unique, highly characterized, and possesses serial samples collected at regular intervals; the unique platforms that will be used have been shown to yield potentially useful biomarkers and can also evaluate existing markers of interest; and this study is powered to identify biomarkers with clinically meaningful performance characteristics.