Abstract
Introduction
SETBP1 mutations have been established as a diagnostic marker in myeloid malignancies and are associated with inferior survival. Since there is limited data on their clinical impact and stability during disease progression, we sought to investigate the relationship between SETBP1 mutations and disease evolution.
Methods
Bidirectional Sanger sequencing of the SETBP1 gene was performed for 442 unselected patients with World Health Organization (WHO) defined myeloid disorders. Follow-up analysis was performed on samples from 123/442 patients to investigate SETBP1 mutation dynamics. Targeted deep next-generation sequencing for a panel of 30 leukemia-associated genes was established to study SETBP1 cooperating mutations.
Results
10/442 patients (2.3%) had SETBP1 hotspot mutations (MDS/MPN, n = 7, sAML, n = 3), whereas four patients (1%) had SETBP1 non-hotspot mutations (MPN, n = 1; MDS, n = 2; sAML, n = 1). The median overall survival for patients with SETBP1 hotspot mutations, SETBP1 non-hotspot mutations, and SETBP1 wild type was 14 (range 0–31), 50 (range 0–71), and 47 months (range 0–402), respectively. In Kaplan–Meier analysis, SETBP1 hotspot mutations were significantly associated with reduced overall survival compared to SETBP1 non-hotspot mutations and the SETBP1 wild type (p < 0.001). All 10 patients with SETBP1 hotspot mutations died from relapse or disease progression. Three of four patients with SETBP1 non-hotspot mutations are alive with stable disease. Cooperating CSF3R and TET2 mutations were most frequently observed in patients with SETBP1 hotspot mutations.
Conclusions
Patients with SETBP1 hotspot mutations suffered from aggressive disease with rapid evolution and inferior overall survival. Patients with SETBP1 non-hotspot mutations had less aggressive disease and a more favorable prognosis. Diagnostic screens for SETBP1 hotspot mutations may help identifying this dismal patient group and treat them in multicenter clinical studies.
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Acknowledgements
The excellent technical assistance of Mrs. Anja Waldau is gratefully acknowledged. In previous research projects on SETBP1, NW was supported by the Dr. Mildred Scheel Stiftung for Krebsforschung (Bonn, Germany).
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This study was funded by the Interdisciplinary Center for Clinical Research (Universitätsklinikum Jena, Germany) with the Junior Project Grant No. J43.
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All authors declare that they have no competing interest.
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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.
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Informed consent was obtained from all individual participants included in the study.
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Winkelmann, N., Schäfer, V., Rinke, J. et al. Only SETBP1 hotspot mutations are associated with refractory disease in myeloid malignancies. J Cancer Res Clin Oncol 143, 2511–2519 (2017). https://doi.org/10.1007/s00432-017-2518-z
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DOI: https://doi.org/10.1007/s00432-017-2518-z