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Nat Genet. 2014 Nov;46(11):1227-32. doi: 10.1038/ng.3095. Epub 2014 Sep 21.

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

Author information

1
1] Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
2
1] Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
3
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
4
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
5
Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.
6
1] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA. [2] Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA. [3] Institute for Precision Medicine, Weill Cornell Medical College, New York, New York, USA.
7
1] Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
8
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
9
Genomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
10
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
11
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
12
1] Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.
13
1] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
14
1] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [3] Department of Medicine, Weill Cornell Medical College, New York, New York, USA.

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.

PMID:
25240281
PMCID:
PMC4249650
DOI:
10.1038/ng.3095
[Indexed for MEDLINE]
Free PMC Article

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