PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors.

TitlePRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors.
Publication TypeJournal Article
Year of Publication2014
AuthorsLee W, Teckie S, Wiesner T, Ran L, Granada CNPrieto, Lin M, Zhu S, Cao Z, Liang Y, Sboner A, Tap WD, Fletcher JA, Huberman KH, Qin L-X, Viale A, Singer S, Zheng D, Berger MF, Chen Y, Antonescu CR, Chi P
JournalNat Genet
Volume46
Issue11
Pagination1227-32
Date Published2014 Nov
ISSN1546-1718
KeywordsBase Sequence, Cell Line, Tumor, Chromatin Immunoprecipitation, Cyclin-Dependent Kinase Inhibitor p16, DNA Methylation, DNA Primers, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomics, Histones, Humans, Immunohistochemistry, Molecular Sequence Data, Mutation, Neurilemmoma, Neurofibromin 1, Polycomb Repressive Complex 2, Real-Time Polymerase Chain Reaction, Sequence Analysis, DNA
Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) represent a group of highly aggressive soft-tissue sarcomas that may occur sporadically, in association with neurofibromatosis type I (NF1 associated) or after radiotherapy. Using comprehensive genomic approaches, we identified loss-of-function somatic alterations of the Polycomb repressive complex 2 (PRC2) components (EED or SUZ12) in 92% of sporadic, 70% of NF1-associated and 90% of radiotherapy-associated MPNSTs. MPNSTs with PRC2 loss showed complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3) and aberrant transcriptional activation of multiple PRC2-repressed homeobox master regulators and their regulated developmental pathways. Introduction of the lost PRC2 component in a PRC2-deficient MPNST cell line restored H3K27me3 levels and decreased cell growth. Additionally, we identified frequent somatic alterations of CDKN2A (81% of all MPNSTs) and NF1 (72% of non-NF1-associated MPNSTs), both of which significantly co-occur with PRC2 alterations. The highly recurrent and specific inactivation of PRC2 components, NF1 and CDKN2A highlights their critical and potentially cooperative roles in MPNST pathogenesis.

DOI10.1038/ng.3095
Alternate JournalNat Genet
PubMed ID25240281
PubMed Central IDPMC4249650
Grant ListR01 CA193837 / CA / NCI NIH HHS / United States
P50CA140146 / CA / NCI NIH HHS / United States
U24-CA143840 / CA / NCI NIH HHS / United States
K08CA151660 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
K08CA140946 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
DP2 CA174499 / CA / NCI NIH HHS / United States
K08 CA151660 / CA / NCI NIH HHS / United States
P50 CA140146 / CA / NCI NIH HHS / United States
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