@article{49d2fa0fb01244888db7a95595297166,
title = "PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors",
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.",
author = "William Lee and Sewit Teckie and Thomas Wiesner and Leili Ran and {Prieto Granada}, {Carlos N.} and Mingyan Lin and Sinan Zhu and Zhen Cao and Yupu Liang and Andrea Sboner and Tap, {William D.} and Fletcher, {Jonathan A.} and Huberman, {Kety H.} and Qin, {Li Xuan} and Agnes Viale and Samuel Singer and Deyou Zheng and Berger, {Michael F.} and Yu Chen and Antonescu, {Cristina R.} and Ping Chi",
note = "Funding Information: Next-generation sequencing and SNP6.0 analysis were performed at the Memorial Sloan Kettering Cancer Center (MSKCC) Genomics Core Facility, Center for Molecular Oncology (CMO). The authors thank members of the cBioPortal team (J. Gao, B. Gross, N. Schultz and C. Sander) for assistance with data analysis and visualization. The authors also thank T. Chan (MSKCC) and HOPP informatics for assistance with data analysis. This work was supported in part by a grant from the US National Institutes of Health (NIH) to W.L. (NCI U24-CA143840), the Harry J. Lloyd Trust–Translational Research grant to T.W., the Charles H. Revson Senior Fellowship to T.W., Jubilaeumsfonds of the Oesterreichische Nationalbank to T.W., grants from the US NIH to P.C. (P50CA140146, Career Development Award and Developmental Research Project.; DP2CA174499; K08CA151660), Y.C. (K08CA140946), L.-X.Q. (P50CA140146), C.R.A. (P50CA140146) and S.S. (P50CA140146), an award from the Sidney Kimmel Foundation to P.C. (Kimmel Scholar Award) and funding from the Cycle for Survival Fund to P.C. Publisher Copyright: {\textcopyright} 2014 Nature America, Inc. All rights reserved.",
year = "2014",
month = nov,
day = "5",
doi = "10.1038/ng.3095",
language = "English (US)",
volume = "46",
pages = "1227--1232",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "11",
}