Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer.
Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer.
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DOI：
10.1371/journal.pone.0015003
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发表时间：
2010-12-07
期刊：
影响因子：
3.7
通讯作者：
Brody EN
中科院分区：
文献类型：
--
作者：
Ostroff RM;Bigbee WL;Franklin W;Gold L;Mehan M;Miller YE;Pass HI;Rom WN;Siegfried JM;Stewart A;Walker JJ;Weissfeld JL;Williams S;Zichi D;Brody EN
肺癌是全球癌症死亡的主要原因。需要新的诊断方法来检测早期肺癌，因为它可以通过手术治愈。然而，大多数病例诊断太迟，无法进行根治性手术。在这里，我们提出了一个全面的肺癌临床生物标志物研究和首次大规模临床应用的一种新的基于适体的蛋白质组学技术，以发现疾病中的血液蛋白质生物标志物。我们对来自4项长期烟草暴露人群非小细胞肺癌（NSCLC）独立研究的1，326名受试者的存档血清样本进行了多中心病例对照研究。在统一方案下收集和处理血清。在第一次活检证实肺癌的8周内和通过手术切除肿瘤之前，从291名患者收集病例血清。从1,035名吸烟≥10包-年的无症状研究参与者中收集对照血清。我们使用新的基于适体的蛋白质组学技术测量了每份样本中的813种蛋白质，鉴定了44种候选生物标志物，并开发了12种蛋白质组（钙粘蛋白-1，CD 30配体，内皮抑制素，HSP 90 α，LRIG 3，MIP-4，多效生长因子，PRKCl，RGM-C，SCF-sR，sL-选择素，和是），其在交叉验证训练中以91%的灵敏度和84%的特异性区分NSCLC和对照，在单独的验证组中以89%的灵敏度和83%的特异性区分NSCLC和对照，对于早期和晚期NSCLC具有相似的性能。这项研究是临床蛋白质组学在高度未满足的临床需求领域的重大进展。我们的分析超过了以前发表的广泛的血清蛋白质组分析平台，包括质谱，抗体阵列，和自身抗体阵列的临床研究中询问的蛋白质组的广度和动态范围。我们的12-生物标志物组的灵敏度和特异性在已发表的蛋白质和基因表达组上有所提高。分类器性能的单独验证提供了反对过度拟合的证据，并鼓励下一个开发阶段，独立验证。这项仔细的研究为开发识别早期肺癌所急需的测试提供了坚实的基础。
Lung cancer is the leading cause of cancer deaths worldwide. New diagnostics are needed to detect early stage lung cancer because it may be cured with surgery. However, most cases are diagnosed too late for curative surgery. Here we present a comprehensive clinical biomarker study of lung cancer and the first large-scale clinical application of a new aptamer-based proteomic technology to discover blood protein biomarkers in disease. We conducted a multi-center case-control study in archived serum samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. Sera were collected and processed under uniform protocols. Case sera were collected from 291 patients within 8 weeks of the first biopsy-proven lung cancer and prior to tumor removal by surgery. Control sera were collected from 1,035 asymptomatic study participants with ≥10 pack-years of cigarette smoking. We measured 813 proteins in each sample with a new aptamer-based proteomic technology, identified 44 candidate biomarkers, and developed a 12-protein panel (cadherin-1, CD30 ligand, endostatin, HSP90α, LRIG3, MIP-4, pleiotrophin, PRKCI, RGM-C, SCF-sR, sL-selectin, and YES) that discriminates NSCLC from controls with 91% sensitivity and 84% specificity in cross-validated training and 89% sensitivity and 83% specificity in a separate verification set, with similar performance for early and late stage NSCLC. This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels. Separate verification of classifier performance provides evidence against over-fitting and is encouraging for the next development phase, independent validation. This careful study provides a solid foundation to develop tests sorely needed to identify early stage lung cancer.