Title | PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Lee 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 |
Journal | Nat Genet |
Volume | 46 |
Issue | 11 |
Pagination | 1227-32 |
Date Published | 2014 Nov |
ISSN | 1546-1718 |
Keywords | Base 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. |
DOI | 10.1038/ng.3095 |
Alternate Journal | Nat Genet |
PubMed ID | 25240281 |
PubMed Central ID | PMC4249650 |
Grant List | R01 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 |
Related Faculty:
Andrea Sboner, Ph.D.