Published ahead of print on August 18, 2005, doi:10.1164/rccm.200505-830OC Am. J. Respir. Crit. Care Med., Volume 172, Number 10, November 2005, 1308-1314 A more recent version of this article appeared on November 15, 2005
Submitted on May 27, 2005 Using Protein Microarray as a Diagnostic Assay for Non-Small Cell Lung CancerLi Zhong1*,1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Kentucky Medical Center, Lexington, KY, USA, 2 Department of Statistics, University of Kentucky, Lexington, KY, USA, 3 Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA, 4 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Kentucky Medical Center, Lexington, KY, USA; Lexington Veteran's Administration Medical Center, Lexington, KY, USA * To whom correspondence should be addressed. E-mail: lzhon2{at}uky.edu.
Rationale: Phenotypic and genotypic heterogeneity of lung cancer likely precludes the identification of a single predictive marker and suggests the importance of identifying and measuring multiple markers. Objectives: We describe the use of fluorescent protein microarray to identify and measure multiple non-small cell lung cancer-associated antibodies and show how simultaneous measurements can be combined into a single diagnostic assay. Methods: T7 phage cDNA libraries of non-small cell lung cancer were first biopanned using normal and non-small cell lung cancer patient plasmas to enrich the component of tumor-associated proteins, and then applied to microarray slides. Two hundred twelve immunogenic phage-expressed proteins were identified from roughly 4000 clones using high-throughput screening with patient plasmas and assayed with 40 cancer and 41 normal plasma samples. Twenty patient and 21 normal plasma samples were randomly chosen and used for statistical determination of predictive value of each putative marker. Statistical analysis identified antibody reactivity to 7 unique phage-expressed proteins that were significantly different (p<0.01) between patient and normal groups. The remaining 20 patient and 20 normal plasma samples were used as an independent test of the predictive ability of the selected markers. Main Results: Measurements of the 5 most predictive phage proteins were combined in a logistic regression model that achieved 90% sensitivity and 95% specificity in prediction of patient samples, while the leave-one-out statistical analysis achieved 88.9% diagnostic accuracy among all 81 samples. Conclusion: Our data indicate that antibody profiling is a promising approach that could achieve a high diagnostic accuracy for non-small cell lung cancer. Key words: Tumor-associated antibodies, Biomarkers, Phage display, Fluorescent array
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