Novel Protein Risk Markers for Lung Cancer

 描述（由申请方提供）：源自肺且在循环血浆中可测量的蛋白质标志物有可能在综合风险评估和筛查过程中补充低剂量计算机断层扫描（LDCT）。基于对来自几个定量血浆分析平台（糖组学、代谢组学、免疫组学和蛋白质组学）的数据的综合分析，我们先前已经确定了一组循环蛋白质生物标志物候选物，其在初始验证研究中能够区分肺癌病例的诊断前血浆与β-胡萝卜素和视黄醇疗效试验（CARET）队列中的对照受试者的血浆。 我们提出的研究的主要目标是确定在CARET队列中鉴定的候选生物标志物是否也可以在医师健康研究（PHS）队列中的临床诊断之前检测癌症。PHS队列的一个独特特征是随访持续时间长，基线采血和病例诊断之间间隔0.5至25年。这允许我们确定标记物相对于诊断时间的性能;即，它们是否是最有用的风险标志物、信号恶化前变化，或作为信号出现恶性肿瘤的早期检测标志物。 本研究的主要目的是通过在从PHS队列中抽取的一组盲态样本中检测这些生物标志物来验证先前鉴定的肺癌候选蛋白质生物标志物组。将使用酶联免疫吸附试验（ELISA）分析入组时采集的基线血浆样本中的每种候选蛋白质生物标志物。然后，我们将比较病例（n=182）和对照组（n=325），在年龄、吸烟和随访持续时间方面匹配，单独和组合（面板）的生物标志物。 本研究的第二个目的是确定适用于两种模式的生物标志物组：1）风险评估，其中我们将确定具有高灵敏度的组，以预测诊断前> 8年的肺癌，并帮助指导关于是否需要LDCT随访的决定;和2）早期检测，其中我们将确定具有高特异性的面板以预测诊断前< 8年的肺癌，作为LDCT的补充，其成本高且具有非常高的灵敏度但特异性低。 本研究的第三个目的是利用纳米颗粒技术开发灵敏、低成本的多反应监测（MRM）检测方法，用于临床环境中经验证的生物标志物的应用。 结论：如果得到验证，一组可以在血液中可行测量的蛋白质生物标志物将提供一种新的工具来评估风险和/或筛查早期肺癌，以便适当地应用化学预防，生活方式改变和治疗措施，减少肺癌的负担。

 DESCRIPTION (provided by applicant): Protein markers originating in the lung and measurable in the circulating plasma have the potential to complement low-dose computed tomography (LDCT) within a comprehensive risk assessment and screening process. Based on integrative analysis of data from several quantitative plasma profiling platforms (glycomics, metabolomics, immunomics, and proteomics), we have previously identified a set of circulating protein biomarker candidates that, in initial validation studies, had the ability to discriminate between pre-diagnostic plasmas of lung cancer cases from those of control subjects in the Beta-Carotene and Retinol Efficacy Trial (CARET) cohort. The main goal of our proposed study is to determine if the candidate biomarkers identified in the CARET cohort also can detect cancer before clinical diagnosis in the Physicians' Health Study (PHS) cohort. A unique feature of the PHS cohort is the long duration of follow-up, with a lapse of 0.5 to 25 years between baseline blood collection and diagnosis of cases. This allows us to determine the performance of the markers in relation to time to diagnosis; i.e., whether they are most useful as markers of risk, signaling pre-malignant changes, or as early detection markers that signal the emergence of malignancy. The primary aim of this study is to validate a panel of previously identified candidate protein biomarkers for lung cancer by testing these biomarkers in a set of blinded samples drawn from the PHS cohort. Baseline plasma samples drawn at enrollment will be analyzed for each candidate protein biomarker using an enzyme-linked immune-sorbent assay (ELISA). We will then compare cases (n=182) and controls (n=325), matched on age, smoking, and duration of follow-up, with respect to the biomarkers, individually and in combination (panel). The second aim of this study is to determine the biomarker panels appropriate for each of two modalities: 1) risk assessment, in which we will determine a panel with high sensitivity to predict lung cancer > 8 years before diagnosis and help guide decisions regarding the need for follow up with LDCT; and 2) early detection, in which we will determine a panel with high specificity to predict lung cancer < 8 years before diagnosis as a complement to LDCT, which is costly and has very high sensitivity but low specificity. The third aim of this study is to utiliz nanoparticle technology to develop sensitive, low-cost multiple reaction monitoring (MRM) assays for the application of validated biomarkers in the clinical setting. Conclusion: If validated, a panel of protein biomarkers that can be feasibly measured in blood will offer a new tool to assess risk and/or screen for early lung cancer so that chemoprevention, lifestyle changes, and treatment measures can be applied as appropriate, reducing the burden of lung cancer.