Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer

• Published in: PloS one Vol. 5; no. 12; p. e15003
• Main Authors: Ostroff, Rachel M, Bigbee, William L, Franklin, Wilbur, Gold, Larry, Mehan, Mike, Miller, York E, Pass, Harvey I, Rom, William N, Siegfried, Jill M, Stewart, Alex, Walker, Jeffrey J, Weissfeld, Joel L, Williams, Stephen, Zichi, Dom, Brody, Edward N
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07-12-2010; Public Library of Science (PLoS)
• Subjects: Algorithms; Aptamers; Autoantibodies; Autoantibodies - chemistry; Autoimmunity; Biology; Biomarkers; Biomarkers - metabolism; Biomarkers, Tumor - metabolism; Biopsy; Blood proteins; Cadherins; Cancer; Cancer diagnosis; Cancer research; Carcinoma, Non-Small-Cell Lung - metabolism; Case-Control Studies; CD30 antigen; Cigarette smoking; Cohort Studies; Disease control; Drug dosages; E-cadherin; Early Detection of Cancer - methods; Endostatin; Gene expression; Health aspects; Heat shock proteins; Humans; Lung cancer; Lung diseases; Lung Neoplasms - metabolism; Mass spectrometry; Mass Spectrometry - methods; Mass spectroscopy; Medical diagnosis; Medical schools; Medical screening; Medicine; Models, Statistical; Non-small cell lung cancer; Non-small cell lung carcinoma; Physics; Pleiotrophin; Proteins; Proteomics; Proteomics - methods; Sensitivity; Sensitivity and Specificity; Smoking; Smoking - adverse effects; Studies; Surgery; Technology; Tobacco; Tumor removal; New York; Pittsburgh Pennsylvania; United States > US; Colorado; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0015003

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.