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. Antonescu & 1 others Ping Chi

Research output: Chapter in Book/Report/Conference proceedingChapter

176 Citations (Scopus)

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)
Title of host publicationNature Genetics
PublisherNature Publishing Group
Pages1227-1232
Number of pages6
Volume46
Edition11
DOIs
StatePublished - Nov 5 2014

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Polycomb Repressive Complex 2
Neurilemmoma
Radiotherapy
Neurofibromatosis 1
Homeobox Genes
Tumor Cell Line
Sarcoma
Histones
Transcriptional Activation
Lysine

ASJC Scopus subject areas

  • Genetics

Cite this

Lee, W., Teckie, S., Wiesner, T., Ran, L., Prieto Granada, C. N., Lin, M., ... Chi, P. (2014). PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. In Nature Genetics (11 ed., Vol. 46, pp. 1227-1232). Nature Publishing Group. https://doi.org/10.1038/ng.3095

PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. / Lee, William; Teckie, Sewit; Wiesner, Thomas; Ran, Leili; Prieto Granada, Carlos N.; Lin, Mingyan; Zhu, Sinan; Cao, Zhen; Liang, Yupu; Sboner, Andrea; Tap, William D.; Fletcher, Jonathan A.; Huberman, Kety H.; Qin, Li Xuan; Viale, Agnes; Singer, Samuel; Zheng, Deyou; Berger, Michael F.; Chen, Yu; Antonescu, Cristina R.; Chi, Ping.

Nature Genetics. Vol. 46 11. ed. Nature Publishing Group, 2014. p. 1227-1232.

Research output: Chapter in Book/Report/Conference proceedingChapter

Lee, W, Teckie, S, Wiesner, T, Ran, L, Prieto Granada, CN, Lin, M, Zhu, S, Cao, Z, Liang, Y, Sboner, A, Tap, WD, Fletcher, JA, Huberman, KH, Qin, LX, Viale, A, Singer, S, Zheng, D, Berger, MF, Chen, Y, Antonescu, CR & Chi, P 2014, PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. in Nature Genetics. 11 edn, vol. 46, Nature Publishing Group, pp. 1227-1232. https://doi.org/10.1038/ng.3095
Lee W, Teckie S, Wiesner T, Ran L, Prieto Granada CN, Lin M et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. In Nature Genetics. 11 ed. Vol. 46. Nature Publishing Group. 2014. p. 1227-1232 https://doi.org/10.1038/ng.3095
Lee, William ; Teckie, Sewit ; Wiesner, Thomas ; Ran, Leili ; Prieto Granada, Carlos N. ; Lin, Mingyan ; Zhu, Sinan ; Cao, Zhen ; Liang, Yupu ; Sboner, Andrea ; Tap, William D. ; Fletcher, Jonathan A. ; Huberman, Kety H. ; Qin, Li Xuan ; Viale, Agnes ; Singer, Samuel ; Zheng, Deyou ; Berger, Michael F. ; Chen, Yu ; Antonescu, Cristina R. ; Chi, Ping. / PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nature Genetics. Vol. 46 11. ed. Nature Publishing Group, 2014. pp. 1227-1232
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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.",
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AU - Lin, Mingyan

AU - Zhu, Sinan

AU - Cao, Zhen

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AU - Sboner, Andrea

AU - Tap, William D.

AU - Fletcher, Jonathan A.

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AU - Singer, Samuel

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