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Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations

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Abstract

Meningiomas are among the most frequent intracranial tumors. The secretory variant of meningioma is characterized by glandular differentiation, formation of intracellular lumina and pseudopsammoma bodies, expression of a distinct pattern of cytokeratins and clinically by pronounced perifocal brain edema. Here we describe whole-exome sequencing analysis of DNA from 16 secretory meningiomas and corresponding constitutional tissues. All secretory meningiomas invariably harbored a mutation in both KLF4 and TRAF7. Validation in an independent cohort of 14 secretory meningiomas by Sanger sequencing or derived cleaved amplified polymorphic sequence (dCAPS) assay detected the same pattern, with KLF4 mutations observed in a total of 30/30 and TRAF7 mutations in 29/30 of these tumors. All KLF4 mutations were identical, affected codon 409 and resulted in a lysine to glutamine exchange (K409Q). KLF4 mutations were not found in 89 non-secretory meningiomas, 267 other intracranial tumors including gliomas, glioneuronal tumors, pituitary adenomas and metastases, 59 peripheral nerve sheath tumors and 52 pancreatic tumors. TRAF7 mutations were restricted to the WD40 domains. While KLF4 mutations were exclusively seen in secretory meningiomas, TRAF7 mutations were also observed in 7/89 (8 %) of non-secretory meningiomas. KLF4 and TRAF7 mutations were mutually exclusive with NF2 mutations. In conclusion, our findings suggest an essential contribution of combined KLF4 K409Q and TRAF7 mutations in the genesis of secretory meningioma and demonstrate a role for TRAF7 alterations in other non-NF2 meningiomas.

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Acknowledgments

We wish to thank Tanja Göck, Kerstin Lindenberg and Diana Rieker for skillful technical assistance. We thank GATC Biotech AG for sequencing services.

Author information

Author notes

  1. Jürgen Kraus

    Present address: Medizinisches Versorgungszentrum für Neurologie und Psychiatrie, Hammersbecker Str. 224a, 28755, Bremen, Germany

Authors and Affiliations

  1. Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany

    David E. Reuss, Felix Sahm, Stefan Pusch, Leonille Schweizer, David Capper, Phillipp Kickingereder, Christian Koelsche & Andreas von Deimling

  2. Clinical Cooperation Unit Neuropathology, German Cancer Institute (DKFZ), Im Neuenheimer Feld 224, 69120, Heidelberg, Germany

    David E. Reuss, Felix Sahm, Stefan Pusch, Jochen Meyer, Christian Hagenlocher, Leonille Schweizer, David Capper, Phillipp Kickingereder, Jana Mucha, Christian Koelsche & Andreas von Deimling

  3. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany

    Rosario M. Piro, Natalie Jäger, Roland Eils & Rainer König

  4. Institute of Pharmacy and Molecular Biotechnology, and Bioquant Center, University of Heidelberg, INF 280, 69120, Heidelberg, Germany

    Rosario M. Piro, Roland Eils & Rainer König

  5. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany

    David T. W. Jones, Marcel Kool & Stefan M. Pfister

  6. Department of Neurosurgery, University of Bonn, Sigmund-Freud-St. 25, 53105, Bonn, Germany

    Matthias Simon

  7. Klinik für Neurochirurgie, Universitätsklinikum des Saarlandes, Kirrberger Str, Homburg, 66421, Saarland, Germany

    Ralf Ketter

  8. Department of Neuropathology, University of Bonn, Sigmund-Freud-St. 25, 53105, Bonn, Germany

    Albert Becker

  9. Department of Neurosurgery, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK

    Thomas Santarius

  10. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK

    Patrick S. Tarpey, Philip J. Stephens & P. Andrew Futreal

  11. Department of Molecular Genome Analysis, German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany

    Ruth Wellenreuther

  12. Department of Neurosurgery, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany

    Doris Lenartz

  13. Department of Neurosurgery, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany

    Christel Herold-Mende

  14. Department for Neuropathology, Institute of Pathology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Christian Hartmann

  15. Department of Neuropathology, Otto von Guericke University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany

    Christian Mawrin

  16. Chirurgische Universitätsklinik, Universität Heidelberg, INF 110, 69120, Heidelberg, Germany

    Nathalia Giese

  17. Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, CB2 0QQ, UK

    V. Peter Collins

  18. German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany

    Otmar D. Wiestler

  19. Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, INF 430, 69120, Heidelberg, Germany

    Stefan M. Pfister

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  1. David E. Reuss
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  34. Andreas von Deimling
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Corresponding author

Correspondence to Andreas von Deimling.

Additional information

Note added in proof During the process of submitting this manuscript, a study published by Clark et al. reported the presence of TRAF7, KLF4, AKT1 and SMO mutations in Non-NF2 meningiomas [6].

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Reuss, D.E., Piro, R.M., Jones, D.T.W. et al. Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol 125, 351–358 (2013). https://doi.org/10.1007/s00401-013-1093-x

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  • DOI: https://doi.org/10.1007/s00401-013-1093-x

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