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

• Published in: Nature genetics Vol. 46; no. 11; pp. 1227 - 1232
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2014; Nature Publishing Group
• Subjects: 45/15; 45/23; 45/61; 45/91; 631/208/212/2166; 631/337/176; 692/699/67/1798; 82/51; Agriculture; Animal Genetics and Genomics; Base Sequence; Biomedicine; Cancer Research; Cell Line, Tumor; Chromatin Immunoprecipitation; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Data analysis; Deoxyribonucleic acid; DNA; DNA Methylation; DNA Primers - genetics; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - genetics; Gene Function; Genetic aspects; Genomics - methods; Health aspects; Histones - metabolism; Human Genetics; Humans; Immunohistochemistry; Inactivation; letter; Molecular Sequence Data; Mutation; Mutation - genetics; Neoplasm Proteins; Neurilemmoma - genetics; Neurofibromin 1 - genetics; Pathogenesis; Peripheral nerve diseases; Physiological aspects; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Proteins; Radiation therapy; Real-Time Polymerase Chain Reaction; Sarcoma; Sequence Analysis, DNA; Transcription Factors; Tumors
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3095

Ping Chi and colleagues identify recurrent inactivating mutations in the PRC2 core components EED and SUZ12 in malignant peripheral nerve sheath tumors. They further show that PRC2 loss is associated with loss of H3K27 trimethylation and aberrant expression of PRC2 target genes and downstream pathways. 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 1 , 2 , 3 . 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.