Journal of Neuro-Oncology

, Volume 127, Issue 3, pp 435–444 | Cite as

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

  • Johannes van de Nes
  • Marco Gessi
  • Antje Sucker
  • Inga Möller
  • Mathias Stiller
  • Susanne Horn
  • Simone L. Scholz
  • Carina Pischler
  • Nadine Stadtler
  • Bastian Schilling
  • Lisa Zimmer
  • Uwe Hillen
  • Richard A. Scolyer
  • Michael E. Buckland
  • Libero Lauriola
  • Torsten Pietsch
  • Andreas Waha
  • Dirk Schadendorf
  • Rajmohan Murali
  • Klaus G. Griewank
Laboratory Investigation

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.

Keywords

Melanocytoma BAP1 GNAQ GNA11 

Notes

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.

Compliance with ethical standards

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.

Supplementary material

11060_2015_2052_MOESM1_ESM.pptx (100 kb)
Supplementary material 1 (PPTX 101 kb)
11060_2015_2052_MOESM2_ESM.xlsx (83 kb)
Supplementary material 2 (XLSX 83 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Johannes van de Nes
    • 1
  • Marco Gessi
    • 4
  • Antje Sucker
    • 2
  • Inga Möller
    • 2
  • Mathias Stiller
    • 2
  • Susanne Horn
    • 2
  • Simone L. Scholz
    • 3
  • Carina Pischler
    • 11
  • Nadine Stadtler
    • 2
  • Bastian Schilling
    • 2
  • Lisa Zimmer
    • 2
  • Uwe Hillen
    • 2
  • Richard A. Scolyer
    • 7
    • 9
    • 10
  • Michael E. Buckland
    • 8
    • 9
  • Libero Lauriola
    • 12
  • Torsten Pietsch
    • 4
  • Andreas Waha
    • 4
  • Dirk Schadendorf
    • 2
  • Rajmohan Murali
    • 5
    • 6
  • Klaus G. Griewank
    • 2
  1. 1.Institute of Neuropathology, University Hospital Essen, West German Cancer CenterUniversity Duisburg-Essen and the German Cancer Consortium (DKTK)Duisburg-EssenGermany
  2. 2.Department of Dermatology, University Hospital Essen, West German Cancer CenterUniversity Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-EssenDuisburg-EssenGermany
  3. 3.Department of Ophthalmology, University Hospital Essen, West German Cancer CenterUniversity Duisburg-Essen and the German Cancer Consortium (DKTK)Duisburg-EssenGermany
  4. 4.Institute of NeuropathologyUniversity of Bonn Medical CenterBonnGermany
  5. 5.Department of PathologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  6. 6.Marie-Josée and Henry R. Kravis Center for Molecular OncologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  7. 7.Tissue Pathology and Diagnostic OncologyCamperdownAustralia
  8. 8.Department of NeuropathologyRoyal Prince Alfred HospitalCamperdownAustralia
  9. 9.The University of SydneyCamperdownAustralia
  10. 10.Melanoma Institute AustraliaNorth SydneyAustralia
  11. 11.Institute of Human GeneticsMedical University of GrazGrazAustria
  12. 12.Department of PathologyCatholic UniversityRomeItaly

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