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

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. AntonescuPing Chi

Research output: Contribution to journalArticle

221 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1227-1232
Number of pages6
JournalNature Genetics
Volume46
Issue number11
DOIs
StatePublished - Nov 5 2014

ASJC Scopus subject areas

  • Genetics

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    Lee, W., Teckie, S., Wiesner, T., Ran, L., Prieto Granada, C. N., Lin, M., Zhu, S., Cao, Z., Liang, Y., Sboner, A., Tap, W. D., Fletcher, J. A., Huberman, K. H., Qin, L. X., Viale, A., Singer, S., Zheng, D., Berger, M. F., Chen, Y., ... Chi, P. (2014). PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nature Genetics, 46(11), 1227-1232. https://doi.org/10.1038/ng.3095