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Targeted next generation sequencing reveals unique mutation profile of primary melanocytic tumors of the central nervous system

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Abstract

Melanocytic tumors originating in the central nervous system (MT-CNS) are rare tumors that generally have a favorable prognosis, however malignant tumors do occur. Pathogenetically MT-CNS are not well characterized. Similar to uveal melanoma and blue nevi, they frequently harbor activating GNAQ or GNA11 mutations. Rare NRAS mutations have also been reported. Other mutations have not yet been described. We analyzed 19 MT-CNS, 7 uveal melanomas and 19 cutaneous melanomas using a targeted next generation sequencing approach analyzing 29 genes known to be frequently mutated in other melanocytic tumors (in particular uveal and cutaneous melanomas). In concordance with previous studies, cutaneous melanoma samples showed frequent NRAS or BRAF mutations, as well as mutations in other genes (e.g. NF1, RAC1, PIK3CA, ARID1A). Metastasized uveal melanomas exhibited mutations in GNAQ, GNA11 and BAP1. In contrast, MT-CNS almost exclusively demonstrated mutations in GNAQ (71 %) or GNA11 (12 %). Interestingly both GNA11 mutations identified were detected in MT-CNS diagnosed as intermediate grade melanocytomas which also recurred. One of these recurrent cases also harbored an inactivating BAP1 mutation and was found to have lost one copy of chromosome 3. Our findings show that while MT-CNS do have GNAQ or GNA11 mutations, they rarely harbor other recurrent mutations found in uveal or cutaneous melanomas. Considering chromosome 3 and BAP1 loss are robust markers of poor prognosis in uveal melanoma, it will prove interesting to determine whether these genomic alterations are also of prognostic significance in MT-CNS.

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Acknowledgments

We would like to thank Marion Schwamborn and Nicola Bielefeld for their excellent technical support. Assistance from staff of Melanoma Institute Australia and Royal Prince Alfred Hospital and funding support from the National Health and Medical Research Council (of the Commonwealth Government of Australia) and the Cancer Institute New South Wales is also gratefully acknowledged.

Funding

This study was not funded by any type of grant or sponsor. There was no external influence on the decision to publish or content of the manuscript.

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Authors and Affiliations

  1. Institute of Neuropathology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Duisburg-Essen, Germany

    Johannes van de Nes

  2. Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Duisburg-Essen, Germany

    Antje Sucker, Inga Möller, Mathias Stiller, Susanne Horn, Nadine Stadtler, Bastian Schilling, Lisa Zimmer, Uwe Hillen, Dirk Schadendorf & Klaus G. Griewank

  3. Department of Ophthalmology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Duisburg-Essen, Germany

    Simone L. Scholz

  4. Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany

    Marco Gessi, Torsten Pietsch & Andreas Waha

  5. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Rajmohan Murali

  6. Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Rajmohan Murali

  7. Tissue Pathology and Diagnostic Oncology, Camperdown, NSW, Australia

    Richard A. Scolyer

  8. Department of Neuropathology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

    Michael E. Buckland

  9. The University of Sydney, Camperdown, NSW, Australia

    Richard A. Scolyer & Michael E. Buckland

  10. Melanoma Institute Australia, North Sydney, NSW, Australia

    Richard A. Scolyer

  11. Institute of Human Genetics, Medical University of Graz, Graz, Austria

    Carina Pischler

  12. Department of Pathology, Catholic University, Rome, Italy

    Libero Lauriola

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  1. Johannes van de Nes
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  2. Marco Gessi
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  3. Antje Sucker
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  4. Inga Möller
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  5. Mathias Stiller
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  6. Susanne Horn
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  7. Simone L. Scholz
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  9. Nadine Stadtler
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  10. Bastian Schilling
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  11. Lisa Zimmer
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  13. Richard A. Scolyer
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  15. Libero Lauriola
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  16. Torsten Pietsch
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  17. Andreas Waha
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  18. Dirk Schadendorf
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  19. Rajmohan Murali
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  20. Klaus G. Griewank
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Corresponding author

Correspondence to Klaus G. Griewank.

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Conflict of interests

Lisa Zimmer has honoraria from Roche, Bristol-Meyers Squibb, and Amgen, and travel support from Merck Sharp and Dohme and Bristol-Meyers Squibb. Bastian Schilling has received honoraria from Roche and travel support as well research funding from Bristol-Myers Squibb. Dirk Schadendorf is on the advisory board or has received honoraria from Roche, Genentech, Novartis, Amgen, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, and Merck Sharp and Dohme. All other authors have nothing to declare.

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van de Nes, J., Gessi, M., Sucker, A. et al. Targeted next generation sequencing reveals unique mutation profile of primary melanocytic tumors of the central nervous system. J Neurooncol 127, 435–444 (2016). https://doi.org/10.1007/s11060-015-2052-2

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