title: Circulating U2 small nuclear RNA fragments as a diagnostic and prognostic biomarker in lung cancer patients.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. jens.koehler@uk-essen.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Köhler
authors.affiliation: Division of Thoracic Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.|German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.affiliation: Division of Thoracic Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.
authors.forename: Thomas Christoph
authors.initials: TC
authors.lastname: Gauler
authors.affiliation: Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany.|Department of Internal Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Nöpel-Dünnebacke
authors.affiliation: Medizinisches Proteom-Center, Bioinformatics/Biostatistics, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Ahrens
authors.affiliation: Division of Thoracic Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.
authors.forename: Andreas-Claudius
authors.initials: AC
authors.lastname: Hoffmann
authors.affiliation: Division of Thoracic Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.|German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kasper
authors.affiliation: Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Nensa
authors.affiliation: Department of Nuclear Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Gomez
authors.affiliation: Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Hahnemann
authors.affiliation: Division of Thoracic Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.|German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Breitenbuecher
authors.affiliation: Department of Thoracic Surgery, Ruhrlandklinik, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Danjouma
authors.initials: D
authors.lastname: Cheufou
authors.affiliation: Department of Interventional Pneumonology, Ruhrlandklinik, West German Lung Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Filiz
authors.initials: F
authors.lastname: Özkan
authors.affiliation: Department of Interventional Pneumonology, Ruhrlandklinik, West German Lung Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Kaid
authors.initials: K
authors.lastname: Darwiche
authors.affiliation: Division of Thoracic Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hoiczyk
authors.affiliation: Institute of Pathology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Reis
authors.affiliation: Department of Thoracic Surgery, Ruhrlandklinik, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Welter
authors.affiliation: Division of Thoracic Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.
authors.forename: Wilfried Ernst Erich
authors.initials: WE
authors.lastname: Eberhardt
authors.affiliation: Medizinisches Proteom-Center, Bioinformatics/Biostatistics, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Eisenacher
authors.affiliation: Department of Pneumonology, Ruhrlandklinik, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Teschler
authors.affiliation: Department of Thoracic Surgery, Ruhrlandklinik, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Stamatis
authors.affiliation: Department of Internal Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Wolff
authors.initials: W
authors.lastname: Schmiegel
authors.affiliation: Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Stephan Albrecht
authors.initials: SA
authors.lastname: Hahn
authors.affiliation: Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany.|Department of Internal Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Baraniskin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000175:diagnosis; D018288:Carcinoma, Small Cell / Q000097:blood / Q000175:diagnosis; D016022:Case-Control Studies; D002908:Chronic Disease; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008171:Lung Diseases / Q000097:blood; D008175:Lung Neoplasms / Q000097:blood* / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D018579:Patient Selection; D011237:Predictive Value of Tests; D011379:Prognosis; D012342:RNA, Small Nuclear / Q000097:blood*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012306:Risk; D012680:Sensitivity and Specificity; D012907:Smoking / Q000009:adverse effects
chemical_list: D014408:Biomarkers, Tumor; D012342:RNA, Small Nuclear; C405484:U2 small nuclear RNA
keywords: Diagnostic; Lung cancer; Prognostic; RNU2-1f; Serum biomarker; Treatment monitoring