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Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence

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Abstract

Epigenetic patterns on the level of DNA methylation have already been shown to separate clinically relevant subgroups of meningiomas. We here set out to identify potential prognostic implications of epigenetic modification on the level of histones with focus on H3K27 trimethylation (H3K27me3). H3K27me3 was assessed by immunohistochemistry on 232 meningiomas from 232 patients. In 194 cases, trimethylation was detected in tumor cells. In 25 cases, staining was limited to vessels while all tumor cells were negative. Finally, 13 cases yielded equivocal staining patterns. Reduced abundance of H3K27me3 in cases with staining limited to vessels was confirmed by mass spectrometry on a subset of cases. Lack of staining for H3K27me3 in all tumor cells was significantly associated with more rapid progression (p = 0.009). In line, H3K27me3-negative cases were associated with a DNA methylation pattern of the more aggressive types among the recently introduced DNA methylation groups. Also, NF2 and SUFU mutations were enriched among cases with complete lack of H3K27me3 staining in tumor cells (p < 0.0001 and p = 0.029, respectively). H3K27me3 staining pattern added significant prognostic insight into WHO grade II cases and in the compound subset of WHO grade I and II cases (p = 0.04 and p = 0.007, respectively). However, it did not further stratify within WHO grade III cases. Collectively, these data indicate that epigenetic modifications beyond DNA methylation are involved in the aggressiveness of meningioma. It also suggests that H3K27me3 immunohistochemistry might be a useful adjunct in meningioma diagnostics, particularly for cases with WHO grade II histology or at the borderline between WHO grade I and II.

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Acknowledgements

The study was supported by grants of the German Cancer Aid (110983, 110670) and the “Else Kröner-Fresenius Stiftung” (2015_A60). We thank Laura Dörner, Antje Habel, Lisa Kreinbihl, and Hai Yen Nguyen for skillful technical assistance.

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Author notes

  1. Leah M. Katz, Thomas Hielscher, Chandra Sen, and Felix Sahm contributed equally as first or senior authors.

Authors and Affiliations

  1. Department of Radiation Oncology, NYU Langone Hospital, New York, NY, USA

    Leah M. Katz, Joshua Silverman & Peter Wu

  2. Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Thomas Hielscher

  3. Division of Neuropathology, Department of Pathology, NYU Langone Hospital, New York, NY, USA

    Benjamin Liechty, David Zagzag & Matija Snuderl

  4. Department of Neurosurgery, NYU Langone Hospital, New York, NY, USA

    Rajeev Sen, John G. Golfinos & Chandra Sen

  5. Department of Neuropathology, University Hospital Heidelberg, 69120, Heidelberg, Germany

    David Reuss, Andreas von Deimling & Felix Sahm

  6. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    David Reuss, Andreas von Deimling & Felix Sahm

  7. Department of Neurosurgery, University Hospital and University of Zurich, Zurich, Switzerland

    Marian Christoph Neidert

  8. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland

    Hans-Georg Wirsching & Michael Weller

  9. Department of Neurosurgery, University Hospital Frankfurt, Frankfurt am Main, Germany

    Peter Baumgarten

  10. Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany

    Christel Herold-Mende

  11. Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Wolfgang Wick

  12. Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany

    Wolfgang Wick

  13. Neurological Institute (Edinger Institute), Goethe University Frankfurt, Frankfurt am Main, Germany

    Patrick N. Harter

  14. German Cancer Consortium (DKTK), Partner Site, Frankfurt/Mainz, Germany

    Patrick N. Harter

  15. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Patrick N. Harter

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  1. Leah M. Katz
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  2. Thomas Hielscher
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Correspondence to Felix Sahm.

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Katz, L.M., Hielscher, T., Liechty, B. et al. Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence. Acta Neuropathol 135, 955–963 (2018). https://doi.org/10.1007/s00401-018-1844-9

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  • DOI: https://doi.org/10.1007/s00401-018-1844-9

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