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Methylation-based classification of benign and malignant peripheral nerve sheath tumors

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Abstract

The vast majority of peripheral nerve sheath tumors derive from the Schwann cell lineage and comprise diverse histological entities ranging from benign schwannomas and neurofibromas to high-grade malignant peripheral nerve sheath tumors (MPNST), each with several variants. There is increasing evidence for methylation profiling being able to delineate biologically relevant tumor groups even within the same cellular lineage. Therefore, we used DNA methylation arrays for methylome- and chromosomal profile-based characterization of 171 peripheral nerve sheath tumors. We analyzed 28 conventional high-grade MPNST, three malignant Triton tumors, six low-grade MPNST, four epithelioid MPNST, 33 neurofibromas (15 dermal, 8 intraneural, 10 plexiform), six atypical neurofibromas, 43 schwannomas (including 5 NF2 and 5 schwannomatosis associated cases), 11 cellular schwannomas, 10 melanotic schwannomas, 7 neurofibroma/schwannoma hybrid tumors, 10 nerve sheath myxomas and 10 ganglioneuromas. Schwannomas formed different epigenomic subgroups including a vestibular schwannoma subgroup. Cellular schwannomas were not distinct from conventional schwannomas. Nerve sheath myxomas and neurofibroma/schwannoma hybrid tumors were most similar to schwannomas. Dermal, intraneural and plexiform neurofibromas as well as ganglioneuromas all showed distinct methylation profiles. Atypical neurofibromas and low-grade MPNST were indistinguishable with a common methylation profile and frequent losses of CDKN2A. Epigenomic analysis finds two groups of conventional high-grade MPNST sharing a frequent loss of neurofibromin. The larger of the two groups shows an additional loss of trimethylation of histone H3 at lysine 27 (H3K27me3). The smaller one retains H3K27me3 and is found in spinal locations. Sporadic MPNST with retained neurofibromin expression did not form an epigenetic group and most cases could be reclassified as cellular schwannomas or soft tissue sarcomas. Widespread immunohistochemical loss of H3K27me3 was exclusively seen in MPNST of the main methylation cluster, which defines it as an additional useful marker for the differentiation of cellular schwannoma and MPNST.

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Authors and Affiliations

  1. Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany

    Manuel Röhrich, Christian Koelsche, Daniel Schrimpf, David Capper, Felix Sahm, Annekathrin Kratz, Andreas von Deimling & David E. Reuss

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

    Manuel Röhrich, Christian Koelsche, Daniel Schrimpf, David Capper, Felix Sahm, Annekathrin Kratz, Jana Reuss, Andreas von Deimling & David E. Reuss

  3. Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Volker Hovestadt

  4. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    David T. W. Jones & Stefan M. Pfister

  5. Genomics and Proteomics Core Facility, Microarray Unit, German Cancer Research Center (DKFZ), INF 580, Heidelberg, Germany

    Melanie Bewerunge-Hudler

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

    Albert Becker

  7. Institute of Neuropathology, Rheinisch-Westfälische Technische Hochschule, Aachen University Hospital, Aachen, Germany

    Joachim Weis

  8. Department of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany

    Christian Mawrin

  9. Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany

    Michel Mittelbronn

  10. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Michel Mittelbronn

  11. Division of Neuropathology, University of California, San Francisco, USA

    Arie Perry

  12. Department of Neurology, University Hospital Hamburg Eppendorf, 20246, Hamburg, Germany

    Victor-Felix Mautner

  13. Department of General Pathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany

    Gunhild Mechtersheimer

  14. Department of Neuropathology, Hannover Medical School, Hannover, Germany

    Christian Hartmann

  15. Department of Pathology, Municipal Hospital Nürnberg, Nuremberg, Germany

    Ali Fuat Okuducu

  16. Department of Neurosurgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Mirko Arp, Marcel Seiz-Rosenhagen & Daniel Hänggi

  17. Institute of Neuropathology, University Hospital, Muenster, Germany

    Stefanie Heim & Werner Paulus

  18. Department of Neuropathology, University Hospital, Tuebingen, Germany

    Jens Schittenhelm

  19. Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany

    Rezvan Ahmadi, Christel Herold-Mende & Andreas Unterberg

  20. Department of Pediatric Oncology, Hematology and Immunology, University Medical Center, Heidelberg, Germany

    Stefan M. Pfister

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  1. Manuel Röhrich
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Corresponding author

Correspondence to David E. Reuss.

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401_2016_1540_MOESM1_ESM.tif

Suppl. Figure 1 Molecular profiling of neurofibromas. The dendrogram depicts the results of unsupervised hierarchical clustering of methylation levels of the 30,000 probes that shows the highest median absolute deviation (MAD) across the beta values. The level of DNA methylation (beta value) is represented with a color scale. CDKN2A deletions are indicated: black indicates presence of the alteration, white indicates absence of the alteration (TIFF 1981 kb)

401_2016_1540_MOESM2_ESM.tif

Suppl. Figure 2 Molecular profiling of schwannomas. The dendrogram depicts the results of unsupervised hierarchical clustering of methylation levels of the 30,000 probes that shows the highest median absolute deviation (MAD) across the beta values. The level of DNA methylation (beta value) is represented with a color scale. Selected chromosomal alterations are indicated: black indicates presence of the alteration, white indicates absence of the alteration (TIFF 2364 kb)

401_2016_1540_MOESM3_ESM.tif

Suppl. Figure 3 a: H3K27me3 immunohistochemistry shows a mixture of positive and negative nuclei in dermal neurofibroma; b: immunohistochemistry shows marked reduction of H3K27me3 in tumor cell nuclei compared to inflammatory cells in MPNST 63354 (TIFF 3842 kb)

401_2016_1540_MOESM4_ESM.xlsx

Supplementary Table 1: Molecular alterations and clinicopathological data from 171 peripheral nerve sheath tumors (XLSX 26 kb)

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Röhrich, M., Koelsche, C., Schrimpf, D. et al. Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol 131, 877–887 (2016). https://doi.org/10.1007/s00401-016-1540-6

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