TY - JOUR
T1 - Methylation-based classification of benign and malignant peripheral nerve sheath tumors
AU - Röhrich, Manuel
AU - Koelsche, Christian
AU - Schrimpf, Daniel
AU - Capper, David
AU - Sahm, Felix
AU - Kratz, Annekathrin
AU - Reuss, Jana
AU - Hovestadt, Volker
AU - Jones, David T.W.
AU - Bewerunge-Hudler, Melanie
AU - Becker, Albert
AU - Weis, Joachim
AU - Mawrin, Christian
AU - Mittelbronn, Michel
AU - Perry, Arie
AU - Mautner, Victor Felix
AU - Mechtersheimer, Gunhild
AU - Hartmann, Christian
AU - Okuducu, Ali Fuat
AU - Arp, Mirko
AU - Seiz-Rosenhagen, Marcel
AU - Hänggi, Daniel
AU - Heim, Stefanie
AU - Paulus, Werner
AU - Schittenhelm, Jens
AU - Ahmadi, Rezvan
AU - Herold-Mende, Christel
AU - Unterberg, Andreas
AU - Pfister, Stefan M.
AU - von Deimling, Andreas
AU - Reuss, David E.
N1 - Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - 450k
KW - Atypical neurofibroma
KW - Clone NFC
KW - Ganglioneuroma
KW - H3K27me3
KW - MPNST
KW - Methylation
KW - NF1
KW - PRC2
KW - Peripheral nerve sheath tumor
KW - Schwannoma
UR - http://www.scopus.com/inward/record.url?scp=84957712268&partnerID=8YFLogxK
U2 - 10.1007/s00401-016-1540-6
DO - 10.1007/s00401-016-1540-6
M3 - Article
C2 - 26857854
AN - SCOPUS:84957712268
SN - 0001-6322
VL - 131
SP - 877
EP - 887
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 6
ER -