title: 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.affiliation: 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.
authors.forename: William
authors.identifier: 0000000195824413
authors.initials: W
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Sewit
authors.initials: S
authors.lastname: Teckie
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiesner
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Leili
authors.initials: L
authors.lastname: Ran
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Carlos N
authors.initials: CN
authors.lastname: Prieto Granada
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Lin
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Sinan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Yupu
authors.initials: Y
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.affiliation: 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.
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Genomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Kety H
authors.initials: KH
authors.lastname: Huberman
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Qin
authors.affiliation: Genomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.affiliation: 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.
authors.forename: Deyou
authors.identifier: 0000000343545337
authors.initials: D
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Chi
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D023281:Genomics / Q000379:methods; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins; D009442:Neurilemmoma / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014157:Transcription Factors
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; C491488:EED protein, human; D006657:Histones; D009363:Neoplasm Proteins; D025542:Neurofibromin 1; C430461:SUZ12 protein, human; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2