Novel Protein Risk Markers for Lung Cancer

 描述(由申请人提供)：起源于肺部并可在循环血浆中测量的蛋白质标记物有可能在全面的风险评估和筛查过程中补充低剂量计算机断层扫描(LDCT)。基于对几个定量血浆图谱平台(糖组学、代谢组学、免疫学和蛋白质组学)数据的综合分析，我们先前已经确定了一组循环蛋白生物标记物候选对象，在初步验证研究中，它们能够区分诊断前肺癌病例的血浆和Beta-胡萝卜素和视黄醇疗效试验(CARET)队列中的对照受试者。我们建议的研究的主要目标是确定Caret队列中确定的候选生物标记物是否也可以在医生健康研究(PHS)队列中的临床诊断之前检测到癌症。PHS队列的一个独特特点是随访时间长，从基线采血到病例诊断之间的间隔为0.5至25年。这使我们能够确定与诊断时间相关的标记物的性能；即，它们是最有用的风险标记物，发出癌前病变的信号，还是作为恶性肿瘤出现的早期检测标记物。这项研究的主要目的是验证一组先前确定的肺癌候选蛋白质生物标记物，方法是在从PHS队列中提取的一组盲法样本中测试这些生物标记物。在注册时抽取的基线血浆样本将使用酶联免疫吸附试验(ELISA)分析每个候选蛋白质生物标记物。然后，我们将比较年龄、吸烟和随访时间相匹配的病例(n=182)和对照组(n=325)，分别和组合(专家小组)的生物标志物。这项研究的第二个目的是确定适合两种模式中每一种的生物标志物小组：1)风险评估，即我们将确定一个在诊断前8年预测肺癌的高灵敏度小组，并帮助指导关于是否需要进行LDCT随访的决策；2)早期检测，我们将确定一个在诊断前8年预测肺癌的高特异性小组，作为LDCT的补充，这是昂贵的，具有非常高的敏感性，但特异性较低。这项研究的第三个目的是利用纳米技术开发灵敏、低成本的多反应监测(MRM)分析方法，以便在临床环境中应用经过验证的生物标志物。结论：如果得到验证，一组可以在血液中可行地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，从而减轻肺癌的负担。

 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.