Jens Köhler1,2, Martin Schuler3,4, Thomas Christoph Gauler3, Stefanie Nöpel-Dünnebacke5,6, Maike Ahrens7, Andreas-Claudius Hoffmann3, Stefan Kasper3,4, Felix Nensa8, Benedikt Gomez9, Maria Hahnemann8, Frank Breitenbuecher3,4, Danjouma Cheufou10, Filiz Özkan11, Kaid Darwiche11, Mathias Hoiczyk3, Henning Reis12, Stefan Welter10, Wilfried Ernst Erich Eberhardt3, Martin Eisenacher7, Helmut Teschler13, Georgios Stamatis10, Wolff Schmiegel6, Stephan Albrecht Hahn5, Alexander Baraniskin5,6. 1. Division of Thoracic Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany. jens.koehler@uk-essen.de. 2. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. jens.koehler@uk-essen.de. 3. Division of Thoracic Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany. 4. German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. 5. Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. 6. Department of Internal Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany. 7. Medizinisches Proteom-Center, Bioinformatics/Biostatistics, Ruhr-University Bochum, Bochum, Germany. 8. Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 9. Department of Nuclear Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 10. Department of Thoracic Surgery, Ruhrlandklinik, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 11. Department of Interventional Pneumonology, Ruhrlandklinik, West German Lung Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 12. Institute of Pathology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 13. Department of Pneumonology, Ruhrlandklinik, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Abstract
PURPOSE: Lung cancer accounts for one in five cancer deaths. Broad screening strategies for high-risk populations are unavailable, and the validation of biomarkers for early cancer detection remains a prime interest. Therefore, we investigated the value of circulating U2 small nuclear RNA fragments (RNU2-1f) as a biomarker for diagnosis, prognosis estimation and treatment monitoring in a large lung cancer cohort. METHODS: We determined RNU2-1f abundance in sera of patients with treatment-naive lung cancer (n = 211, 25.6 % early stage), chronic lung disease (n = 56) and healthy controls (n = 58) by reverse transcription quantitative PCR. Initial levels and changes after one chemotherapy cycle were correlated with treatment outcomes in patient subsets. RESULTS: Relative serum RNU2-1f expression levels (REL) were elevated in lung cancer patients compared with patients with chronic lung disease and healthy controls (p < 0.0001). The area under the receiver operating characteristic curve for the complete data set (lung cancer vs. healthy) was 0.91 (95 % CI 0.87-0.95). By applying a REL of -4.505 as diagnostic cutoff (Youden's criterion), sensitivity and specificity reached 0.86 and 0.81, respectively. To determine the generalization error, in a subsampling study, sensitivity and specificity were estimated as 0.82 and 0.77 for the application to future, independent samples. High initial RNU2-1f REL were associated with shorter median survival in stage IIIB/IV disease (RNU2-1fhigh = 228 days/RNU2-1flow = 484 days; p = 0.009, log-rank test, HR1.43 95 % CI 1.23-1.66). Multivariate analysis confirmed RNU2-1f as an independent prognostic factor. Patients with subsequent RNU2-1f reduction had a trend toward better treatment outcome. CONCLUSIONS: Serum RNU2-1f may serve as a biomarker for lung cancer detection, prognosis prediction and treatment monitoring.
PURPOSE:Lung cancer accounts for one in five cancer deaths. Broad screening strategies for high-risk populations are unavailable, and the validation of biomarkers for early cancer detection remains a prime interest. Therefore, we investigated the value of circulating U2 small nuclear RNA fragments (RNU2-1f) as a biomarker for diagnosis, prognosis estimation and treatment monitoring in a large lung cancer cohort. METHODS: We determined RNU2-1f abundance in sera of patients with treatment-naive lung cancer (n = 211, 25.6 % early stage), chronic lung disease (n = 56) and healthy controls (n = 58) by reverse transcription quantitative PCR. Initial levels and changes after one chemotherapy cycle were correlated with treatment outcomes in patient subsets. RESULTS: Relative serum RNU2-1f expression levels (REL) were elevated in lung cancerpatients compared with patients with chronic lung disease and healthy controls (p < 0.0001). The area under the receiver operating characteristic curve for the complete data set (lung cancer vs. healthy) was 0.91 (95 % CI 0.87-0.95). By applying a REL of -4.505 as diagnostic cutoff (Youden's criterion), sensitivity and specificity reached 0.86 and 0.81, respectively. To determine the generalization error, in a subsampling study, sensitivity and specificity were estimated as 0.82 and 0.77 for the application to future, independent samples. High initial RNU2-1f REL were associated with shorter median survival in stage IIIB/IV disease (RNU2-1fhigh = 228 days/RNU2-1flow = 484 days; p = 0.009, log-rank test, HR1.43 95 % CI 1.23-1.66). Multivariate analysis confirmed RNU2-1f as an independent prognostic factor. Patients with subsequent RNU2-1f reduction had a trend toward better treatment outcome. CONCLUSIONS: Serum RNU2-1f may serve as a biomarker for lung cancer detection, prognosis prediction and treatment monitoring.
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