Molecular Epidemiology and Lung Cancer: A Nested Case-Control Study

描述（由申请方提供）：拟议研究的广泛目的是通过鉴定具有识别早期疾病潜力的蛋白质表达模式来早期检测肺癌。该研究在前瞻性哈佛医师健康研究（PHS）中“嵌套”了一项病例对照研究，以确定健康个体血液中的生物标志物是否可以检测到几年或几十年后会出现的早期疾病。具体目标：我们的目标是检验以下假设：1）来自后来发展肺癌的受试者（病例）的基线血液样品将在其蛋白质表达模式方面与被随访相同时间段并且在招募时具有相同吸烟状态但未发展肺癌的受试者的样品显著不同（对照），使得可以鉴定具有足够灵敏度和特异性（>80%）的“总体”区分模式以用作早期疾病的潜在生物标志物。2)来自后来发展为非小细胞肺癌（NSCLC）的受试者的基线血液样品在其蛋白质表达模式方面与对照样品显著不同，使得可以鉴定具有更高灵敏度和特异性（>85%）的“特异性”区分模式以用作早期NSCLC的潜在生物标志物。虽然许多研究已经证明了蛋白质组学在肺癌早期检测中的潜力，但样本量较小，没有一项研究涉及良好表征的前瞻性队列，并且在确定特定标志物时，研究与研究之间不一致。没有人系统地评估生物标志物的有效性方面的敏感性和特异性的模式下的不同情况下的时间从抽血诊断，组织学，阶段，或吸烟状态。这项研究是验证它们作为肺癌早期检测工具的重要一步。研究设计和方法：将从PHS储存的“登记”样本中选择350例病例和700例匹配对照的基线血样，并分析蛋白质表达模式。已获得每例受试者的详细吸烟、环境、健康和饮食史（基线和随访）。初步研究已经证明了哥伦比亚大学、哈佛大学和NCI/FDA之间合作的可行性，并产生了直接支持所有研究目标的数据。肺癌是美国和世界范围内癌症死亡的主要原因，在美国每年夺去超过162，000人的生命。该提案符合NIH、NCI和NIEHS减轻疾病负担的使命，也符合NCI和NIEHS强调推进的战略领域：癌症预防、早期检测和预测、分子流行病学以及临床前风险的新生物标志物的验证。

DESCRIPTION (provided by applicant): The broad objective of the proposed study is the early detection of lung cancer through the identification of patterns of protein expression with the potential to identify early disease. The research "nests" a case-control study within the prospective Harvard Physicians Health Study (PHS) to determine whether biomarkers in blood of healthy individuals can detect early disease that would manifest itself years or decades later. Specific Aims: Our aims are to test the following hypotheses: 1) The baseline blood samples from subjects who later develop lung cancer (cases) will differ significantly with respect to their patterns of protein expression from samples of subjects who are followed for the same period of time and have the same smoking status at enrollment but do not develop lung cancer (controls), such that an "overall" discriminating pattern can be identified that has adequate sensitivity and specificity (>80%) to serve as a potential biomarker of early disease. 2) The baseline blood samples from subjects who later develop Non-Small Cell Lung Cancer (NSCLC) will differ significantly with respect to their patterns of protein expression from samples of controls, such that a "specific" discriminating pattern can be identified that has higher sensitivity and specificity (>85%) to serve as a potential biomarker of early NSCLC. While a number of studies have demonstrated the potential of proteomics in early detection of lung cancer, the sample sizes have been small, none have involved well characterized prospective cohorts, and the specific markers, when identified, have been inconsistent from study to study. None has systematically assessed biomarker validity in terms of the sensitivity and specificity of the patterns under different circumstances of time from blood draw to diagnosis, histology, stage, or smoking status. This research is an essential step in their validation as tools in early detection of lung cancer. Research design and methods: Baseline blood samples from 350 cases and 700 matched controls will be selected from stored "enrollment" samples from the PHS and analyzed for patterns of protein expression. Detailed smoking, environmental, health and dietary histories (baseline and follow-up) have been obtained on each subject. Preliminary studies have demonstrated the feasibility of this collaboration between Columbia University, Harvard University, and the NCI/FDA and have generated data directly supporting all of the research aims. Lung cancer is the leading cause of death from cancer in the U.S. and worldwide and claims over 162,000 lives every year in the U.S. The proposal fits within the mission of the NIH, NCI, and NIEHS to reduce the burden of illness and within the NCI's and NIEHS' strategic areas highlighted for advancement: cancer prevention, early detection and prediction, molecular epidemiology, and validation of new biomarkers of preclinical risk.