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Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells

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Abstract

Ganglioglioma is a rare CNS tumor with a benign biological behavior. Recently, the BRAF V600E mutation was identified in approximately 20 % of gangliogliomas. Here, we analyzed a total of 71 gangliogliomas for BRAF V600E mutational status by VE1 immunohistochemistry and direct DNA sequencing. The BRAF V600E mutation was detected in 41/71 (58 %) gangliogliomas by immunohistochemistry. DNA sequencing was concordant in 60 of 62 analyzed cases. BRAF status was compared with clinical, histological and immunohistochemical data. Presence of the BRAF V600E mutation was associated with expression of synaptophysin in the tumor (p = 0.0008), presence of dysplastic neurons (p = 0.011) and lymphocytic cuffs (p = 0.018), and with younger age (p = 0.0054). Extensive hemosiderin deposition within the tumor was significantly associated with BRAF wild-type status (p = 0.042). No significant association was found with proliferation (p = 0.053), presence of phospho ERK (p = 0.1) or senescence marker p16INK4a (p = 0.22). Using VE1, we localized the BRAF V600E-mutated protein predominantly to the neuronal compartment, indicating that BRAF mutations occur in cells that have the capacity to differentiate into ganglionic cells. In many cases mutant BRAF is additionally expressed by the glial compartment, indicating that in these cases the cell targeted by BRAF mutation was likely capable of differentiating along both the ganglionic and glial lineages. No cases with an exclusive expression of BRAF V600E in the glial compartment were observed. Thus, using VE1 we identified the neuronal compartment as an essential part of this mixed glioneuronal tumor.

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Acknowledgments

The authors thank Tanja Göck, Diana Rieker and Victoria Zeller for preparation of immunohistochemical stainings and John Moyers for photo-micrographic assistance.

Conflict of interest

D.C. and A.v.D. have applied for a patent on the diagnostic use of BRAF V600E mutant-specific antibody VE1. All terms are being managed by the German Cancer Research Center in accordance with its conflict of interest policies.

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Authors and Affiliations

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

    Christian Koelsche, Andreas von Deimling & David Capper

  2. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany

    Christian Koelsche, Andreas von Deimling & David Capper

  3. Institute of Neurology, Medical University of Vienna, 1090, Vienna, Austria

    Adelheid Wöhrer

  4. Institute of Neuropathology, University Hospital Münster, 48149, Münster, Germany

    Astrid Jeibmann

  5. Department of Neuropathology Institute of Pathology and Neuropathology, University of Tübingen, 72076, Tübingen, Germany

    Jens Schittenhelm

  6. Department of Neurosurgery, Medical Faculty of the Ruhr University Bochum, 44892, Bochum, Germany

    Genevieve Schindler

  7. Comprehensive Cancer Center, Medical University of Vienna, 1090, Vienna, Austria

    Matthias Preusser

  8. Department of Medicine I, Medical University of Vienna, 1090, Vienna, Austria

    Matthias Preusser

  9. Institute of Pathology, University of Heidelberg, 69120, Heidelberg, Germany

    Felix Lasitschka

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  1. Christian Koelsche
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Correspondence to Andreas von Deimling.

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Koelsche, C., Wöhrer, A., Jeibmann, A. et al. Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. Acta Neuropathol 125, 891–900 (2013). https://doi.org/10.1007/s00401-013-1100-2

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