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Acta Neuropathologica

, Volume 131, Issue 6, pp 877–887 | Cite as

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

  • Manuel Röhrich
  • Christian Koelsche
  • Daniel Schrimpf
  • David Capper
  • Felix Sahm
  • Annekathrin Kratz
  • Jana Reuss
  • Volker Hovestadt
  • David T. W. Jones
  • Melanie Bewerunge-Hudler
  • Albert Becker
  • Joachim Weis
  • Christian Mawrin
  • Michel Mittelbronn
  • Arie Perry
  • Victor-Felix Mautner
  • Gunhild Mechtersheimer
  • Christian Hartmann
  • Ali Fuat Okuducu
  • Mirko Arp
  • Marcel Seiz-Rosenhagen
  • Daniel Hänggi
  • Stefanie Heim
  • Werner Paulus
  • Jens Schittenhelm
  • Rezvan Ahmadi
  • Christel Herold-Mende
  • Andreas Unterberg
  • Stefan M. Pfister
  • Andreas von Deimling
  • David E. ReussEmail author
Original Paper

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.

Keywords

MPNST Atypical neurofibroma Schwannoma Ganglioneuroma Peripheral nerve sheath tumor Methylation 450k PRC2 NF1 Clone NFC H3K27me3 

Supplementary material

401_2016_1540_MOESM1_ESM.tif (1.9 mb)
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 (2.3 mb)
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 (3.8 mb)
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 (26 kb)
Supplementary Table 1: Molecular alterations and clinicopathological data from 171 peripheral nerve sheath tumors (XLSX 26 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Manuel Röhrich
    • 1
    • 2
  • Christian Koelsche
    • 1
    • 2
  • Daniel Schrimpf
    • 1
    • 2
  • David Capper
    • 1
    • 2
  • Felix Sahm
    • 1
    • 2
  • Annekathrin Kratz
    • 1
    • 2
  • Jana Reuss
    • 2
  • Volker Hovestadt
    • 3
  • David T. W. Jones
    • 4
  • Melanie Bewerunge-Hudler
    • 5
  • Albert Becker
    • 6
  • Joachim Weis
    • 7
  • Christian Mawrin
    • 8
  • Michel Mittelbronn
    • 9
    • 10
  • Arie Perry
    • 11
  • Victor-Felix Mautner
    • 12
  • Gunhild Mechtersheimer
    • 13
  • Christian Hartmann
    • 14
  • Ali Fuat Okuducu
    • 15
  • Mirko Arp
    • 16
  • Marcel Seiz-Rosenhagen
    • 16
  • Daniel Hänggi
    • 16
  • Stefanie Heim
    • 17
  • Werner Paulus
    • 17
  • Jens Schittenhelm
    • 18
  • Rezvan Ahmadi
    • 19
  • Christel Herold-Mende
    • 19
  • Andreas Unterberg
    • 19
  • Stefan M. Pfister
    • 4
    • 20
  • Andreas von Deimling
    • 1
    • 2
  • David E. Reuss
    • 1
    • 2
    Email author
  1. 1.Department of Neuropathology, Institute of PathologyUniversity of HeidelbergHeidelbergGermany
  2. 2.Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK)German Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Division of Molecular Genetics, German Cancer Consortium (DKTK)German Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Division of Pediatric Neurooncology, German Cancer Consortium (DKTK)German Cancer Research Center (DKFZ)HeidelbergGermany
  5. 5.Genomics and Proteomics Core Facility, Microarray UnitGerman Cancer Research Center (DKFZ), INF 580HeidelbergGermany
  6. 6.Institute of NeuropathologyUniversity Medical CenterBonnGermany
  7. 7.Institute of Neuropathology, Rheinisch-Westfälische Technische HochschuleAachen University HospitalAachenGermany
  8. 8.Department of NeuropathologyOtto-von-Guericke UniversityMagdeburgGermany
  9. 9.Institute of Neurology (Edinger Institute)Goethe UniversityFrankfurtGermany
  10. 10.German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  11. 11.Division of NeuropathologyUniversity of CaliforniaSan FranciscoUSA
  12. 12.Department of NeurologyUniversity Hospital Hamburg EppendorfHamburgGermany
  13. 13.Department of General Pathology, Institute of PathologyUniversity of HeidelbergHeidelbergGermany
  14. 14.Department of NeuropathologyHannover Medical SchoolHannoverGermany
  15. 15.Department of PathologyMunicipal Hospital NürnbergNurembergGermany
  16. 16.Department of Neurosurgery, Universitätsmedizin Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
  17. 17.Institute of NeuropathologyUniversity HospitalMuensterGermany
  18. 18.Department of NeuropathologyUniversity HospitalTuebingenGermany
  19. 19.Department of NeurosurgeryUniversity of HeidelbergHeidelbergGermany
  20. 20.Department of Pediatric Oncology, Hematology and ImmunologyUniversity Medical CenterHeidelbergGermany

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