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Myelodysplastic syndrome

Recurrent somatic mutations are rare in patients with cryptic dyskeratosis congenita

Leukemia volume 32, pages 1762–1767 (2018)Cite this article

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Abstract

Dyskeratosis congenita (DKC) is a paradigmatic telomere disorder characterized by substantial and premature telomere shortening, bone marrow failure, and a dramatically increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). DKC can occur as a late-onset, so-called cryptic form, with first manifestation in adults. Somatic MDS-related mutations are found in up to 35% of patients with acquired aplastic anemia (AA), especially in patients with short telomeres. The aim of our study was to investigate whether cryptic DKC is associated with an increased incidence of MDS-related somatic mutations, thereby linking the accelerated telomere shortening with the increased risk of MDS/AML. Samples from 15 adult patients (median age: 42 years, range: 23–60 years) with molecularly confirmed cryptic DKC were screened using next-generation gene panel sequencing to detect MDS-related somatic variants. Only one of the 15 patients (7%) demonstrated a clinically relevant MDS-related somatic variant. This incidence was dramatically lower than formerly described in acquired AA. Based on our data, we conclude that clonal evolution of subclones carrying MDS-related mutations is not the predominant mechanism for MDS/AML initiation in adult cryptic DKC patients.

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Acknowledgements

We are thankful to Lucia Vankann, Kristina Feldberg and Stephan Klinkenberg for their excellent technical assistance. We thank Kim Kricheldorf for the excellent administration of the “Aachen Telomeropathy Registry”. This work was partly supported by a grant from “Lichterzellen e.V.” (THB).

Author contributions

MK: Performed the experiments, analyzed and interpreted the data and wrote the manuscript. AM: Performed the experiments and analyzed the data. MW: Provided patient samples, clinical data and interpreted the data. MSVF, A-SB, IH: Performed the experiments and interpreted the data. WB, MK, MR, SC, JB, MS, JB, MPR, CMW: Provided patient samples, clinical data and interpreted the data. SK, MB, IK, MS: Performed the experiments, analyzed and interpreted the data. THB co-planned the study, analyzed and interpreted the data and wrote the manuscript; FB conceived and planned the study design, interpreted the data, and wrote the manuscript.

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    Authors and Affiliations

    1. Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany

      Martin Kirschner, Angela Maurer, Monica S. Ventura Ferreira, Anne-Sophie Bouillon, Insa Halfmeyer, Steffen Koschmieder, Mirle Schemionek, Tim H. Brümmendorf & Fabian Beier

    2. Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Hospital Freiburg, Freiburg, Germany

      Marcin W. Wlodarski

    3. Department of Hematology and Oncology, Justus-Liebig University, Giessen, Germany

      Wolfgang Blau

    4. Center for Interstitial and Rare Lung Diseases, Pneumology and Respiratory Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany

      Michael Kreuter

    5. Department of Paediatric Pulmonology, Allergy and Cystic Fibrosis, Children’s Hospital, Goethe-University, Frankfurt, Germany

      Martin Rosewich

    6. Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Hospital Regensburg, Regensburg, Germany

      Selim Corbacioglu

    7. Department of Hematology, Medical Oncology, & Pneumology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

      Joachim Beck & Markus P. Radsak

    8. Department of Hematology and Oncology, University Hospital Charité, Berlin, Germany

      Michaela Schwarz

    9. Department of Hematology and Oncology, University Hospital Saarland, Homburg, Germany

      Jörg Bittenbring

    10. Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland

      Christian Matthias Wilk

    11. Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany

      Matthias Begemann & Ingo Kurth

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    These authors contributed equally: Tim H. Brümmendorf, Fabian Beier.

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    Kirschner, M., Maurer, A., Wlodarski, M.W. et al. Recurrent somatic mutations are rare in patients with cryptic dyskeratosis congenita. Leukemia 32, 1762–1767 (2018). https://doi.org/10.1038/s41375-018-0125-x

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