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Circulating U2 small nuclear RNA fragments as a diagnostic and prognostic biomarker in lung cancer patients

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

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.

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Acknowledgments

We thank Andrea Reinert, Sabrina Schilling, Jeannette Phasue, Stephanie Meyer and Malte Vogelsang for technical assistance.

Funding

This study was supported by the Ministry of Science of North Rhine-Westphalia, Germany (Grant number: PURE).

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Correspondence to Jens Köhler.

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Conflict of interest

Jens Köhler received consultancy honoraria for writing review articles on Afatinib from Boehringer-Ingelheim and travel grants from Roche, Amgen and Lilly. He received a Mildred-Scheel-Postdoctoral Fellowship grant from the German Cancer Aid Foundation. Martin Schuler received institutional research grants from Boehringer Ingelheim and Novartis and consultancy honoraria from Boehringer-Ingelheim, Celgene, Novartis and Lilly. Thomas Christoph Gauler is a board member of Merck Serono and Novartis and received consultancy honoraria from Novartis, Roche and Bayer. He also received institutional grants from Boehringer-Ingelheim and Merck Serono, travel expenses from Merck Serono and payment for lectures from Novartis, Bayer and Roche. He owns stocks in Bayer AG. Maike Ahrens received an institutional grant from the Ministry of Science of North Rhine-Westphalia, Germany (Grant number: PURE). She is furthermore funded by de.NBI, FKZ 031 A 534A, a project of the ‘Bundesministerium für Bildung und Forschung’ (BMBF). Stefan Kasper received consultancy honoraria from Roche, Bayer, Merck, Amgen, Sanofi and Lilly. He received a grant from Merck and payment for lectures from Roche, Merck, Amgen and Sanofi. He received travel/meeting expenses from Roche, Merck, Amgen, Lilly and Sanofi. Wilfried Ernst Erich Eberhardt received consultancy honoraria from BMS, Eli Lilly, Boehringer-Ingelheim, Roche, Pfizer, Novartis, Astra Zeneca, Merck, GSK, Bayer, Aestellas. He also received grants from Eli Lilly and payment for lectures from BMS, Roche, Novartis, Pfizer, Astra Zeneca, Eli Lilly, Bayer, Boehringer Ingelheim, Merck. Martin Eisenacher received institutional grants from the Ministry of Science of North Rhine-Westphalia, Germany (Grant number: PURE) and the German Ministry of Education and Research (BMBF) (“German network for bioinformatics—conception phase”, 4/2014–6/2014). Wolff Schmiegel holds a patent (DE 10 2010 046 866.5) on the use of microRNAs as a diagnostic tool. Stephan Albrecht Hahn received an institutional grant from the Ministry of Science of North Rhine-Westphalia, Germany (Grant number: PURE). Alexander Baraniskin holds a patent (DE 10 2010 046 866.5) on the use of microRNAs as a diagnostic tool and the remaining authors declares that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The sample collection was approved by the local ethical committee of the University Duisburg-Essen (reference number 11-4817-BO) and the institutional review board.

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Informed consent was obtained from all individual participants included in the study.

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Köhler, J., Schuler, M., Gauler, T.C. et al. Circulating U2 small nuclear RNA fragments as a diagnostic and prognostic biomarker in lung cancer patients. J Cancer Res Clin Oncol 142, 795–805 (2016). https://doi.org/10.1007/s00432-015-2095-y

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