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.

• Authors: William Lee, Sewit Teckie, Thomas Wiesner, Leili Ran, Carlos N Prieto Granada, Mingyan Lin, Sinan Zhu, Zhen Cao, Yupu Liang, Andrea Sboner, William D Tap, Jonathan A Fletcher, Kety H Huberman, Li-Xuan Qin, Agnes Viale, Samuel Singer, Deyou Zheng, Michael F Berger, Yu Chen, Cristina R Antonescu, Ping Chi
• Journal: Nature genetics (Nat Genet) Vol. 46 Issue 11 Pg. 1227-32 (Nov 2014) ISSN: 1546-1718 [Electronic] United States
• PMID: 25240281 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p16
• DNA Primers
• EED protein, human
• Histones
• Neoplasm Proteins
• Neurofibromin 1
• SUZ12 protein, human
• Transcription Factors
• Polycomb Repressive Complex 2

Topics

• Base Sequence
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Cyclin-Dependent Kinase Inhibitor p16 (genetics)
• DNA Methylation
• DNA Primers (genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (genetics)
• Genomics (methods)
• Histones (metabolism)
• Humans
• Immunohistochemistry
• Molecular Sequence Data
• Mutation (genetics)
• Neoplasm Proteins
• Neurilemmoma (genetics)
• Neurofibromin 1 (genetics)
• Polycomb Repressive Complex 2 (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Sequence Analysis, DNA
• Transcription Factors