title: Methylation-based classification of benign and malignant peripheral nerve sheath tumors.
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.
authors: Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Manuel
authors: M
authors: Röhrich
authors: Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Christian
authors: C
authors: Koelsche
authors: Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Daniel
authors: D
authors: Schrimpf
authors: Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: David
authors: D
authors: Capper
authors: Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Felix
authors: F
authors: Sahm
authors: Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Annekathrin
authors: A
authors: Kratz
authors: Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Jana
authors: J
authors: Reuss
authors: Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Volker
authors: V
authors: Hovestadt
authors: Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: David T W
authors: DT
authors: Jones
authors: Genomics and Proteomics Core Facility, Microarray Unit, German Cancer Research Center (DKFZ), INF 580, Heidelberg, Germany.
authors: Melanie
authors: M
authors: Bewerunge-Hudler
authors: Institute of Neuropathology, University Medical Center, Bonn, Germany.
authors: Albert
authors: A
authors: Becker
authors: Institute of Neuropathology, Rheinisch-Westfälische Technische Hochschule, Aachen University Hospital, Aachen, Germany.
authors: Joachim
authors: J
authors: Weis
authors: Department of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany.
authors: Christian
authors: C
authors: Mawrin
authors: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Michel
authors: M
authors: Mittelbronn
authors: Division of Neuropathology, University of California, San Francisco, USA.
authors: Arie
authors: A
authors: Perry
authors: Department of Neurology, University Hospital Hamburg Eppendorf, 20246, Hamburg, Germany.
authors: Victor-Felix
authors: VF
authors: Mautner
authors: Department of General Pathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors: Gunhild
authors: G
authors: Mechtersheimer
authors: Department of Neuropathology, Hannover Medical School, Hannover, Germany.
authors: Christian
authors: C
authors: Hartmann
authors: Department of Pathology, Municipal Hospital Nürnberg, Nuremberg, Germany.
authors: Ali Fuat
authors: AF
authors: Okuducu
authors: Department of Neurosurgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Mirko
authors: M
authors: Arp
authors: Department of Neurosurgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Marcel
authors: M
authors: Seiz-Rosenhagen
authors: Department of Neurosurgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Daniel
authors: D
authors: Hänggi
authors: Institute of Neuropathology, University Hospital, Muenster, Germany.
authors: Stefanie
authors: S
authors: Heim
authors: Institute of Neuropathology, University Hospital, Muenster, Germany.
authors: Werner
authors: W
authors: Paulus
authors: Department of Neuropathology, University Hospital, Tuebingen, Germany.
authors: Jens
authors: J
authors: Schittenhelm
authors: Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors: Rezvan
authors: R
authors: Ahmadi
authors: Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors: Christel
authors: C
authors: Herold-Mende
authors: Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors: Andreas
authors: A
authors: Unterberg
authors: Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Pediatric Oncology, Hematology and Immunology, University Medical Center, Heidelberg, Germany.
authors: Stefan M
authors: SM
authors: Pfister
authors: Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Andreas
authors: A
authors: von Deimling
authors: Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. david.reuss@med.uni-heidelberg.de.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. david.reuss@med.uni-heidelberg.de.
authors: David E
authors: DE
authors: Reuss
mesh_terms: D006801:Humans; D008745:Methylation; D018317:Nerve Sheath Neoplasms / Q000145:classification / Q000378:metabolism / Q000473:pathology*; D009442:Neurilemmoma / Q000145:classification / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D017253:Neurofibromatoses / Q000145:classification / Q000378:metabolism / Q000473:pathology*; D025542:Neurofibromin 1 / Q000378:metabolism; D012509:Sarcoma / Q000473:pathology; D012878:Skin Neoplasms / Q000145:classification / Q000378:metabolism / Q000473:pathology*
chemical_list: D025542:Neurofibromin 1
keywords: 450k; Atypical neurofibroma; Clone NFC; Ganglioneuroma; H3K27me3; MPNST; Methylation; NF1; PRC2; Peripheral nerve sheath tumor; Schwannoma