Malignant Peripheral Nerve Sheath Tumors: From Epigenome to Bedside

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas typically developing in the context of neurofibromatosis type 1 (NF-1). With the exception of surgical resection, these tumors are resistant to all current therapies, and unresectable, recurrent, or metastatic tumors are considered incurable. Preclinical studies have identified several novel candidate molecular targets for therapeutic intervention, but, to date, targeted therapies have proven ineffective. Recent studies have identified recurrent mutations in polycomb repressive complex 2 (PRC2) core components, embryonic ectoderm development protein (EED) and suppressor of zeste 12 homolog (SUZ12), in MPNST. These mutations result in global loss of the histone H3 lysine 27 trimethylation epigenetic mark, normally deposited by PRC2, and subsequent gain in acetylation at this residue. This altered chromatin state has been shown to promote MPNST malignancy; however, acetylation at this residue sensitizes MPNSTs to BRD4 and bromodomain and extra-terminal domain inhibition. Interestingly, the catalytic component of PRC2, enhancer of zeste homolog 2 (EZH2), is not mutated in MPNST, hinting that a noncanonical, PRC2-independent function of EZH2 may play a role in this cancer. This review examines the pathobiology of MPNST, the contribution of PRC2 subunits to this process, and the prospects for PRC2-related therapies for this cancer. Implications: Identification of mutations in the PRC2 components EED and SUZ12 in the majority of MPNSTs may imply noncanonical oncogenic activities of the intact component, EZH2, and provide new opportunities for therapeutic intervention.

CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets

“…MPNSTs can develop sporadically (50%), most commonly in middle to advanced aged patients, or in association with NF1, a neurological cancer predisposition syndrome [38]. NF1 is an autosomal dominant condition that occurs through germline loss-of-function mutation of the neurofibromin 1 gene (NF1), which as noted above ultimately results in hyperactivation of Ras [77]. NF1 patients display a mosaic of clinical manifestations, most notably including the development of benign lesions called neurofibromas (NFs).…”

“…Both sporadic and NF1-associated MPNSTs have complex karyotypes characterized by NF1-inactivating mutations along with frequent genetic disruptions of CDKN2A and polycomb repressor complex-2 (PRC2) components, SUZ12 or EED [78,80]. Inactivation of PRC2, which causes loss of histone H3 lysine 27 (H3K27) tri-methylation and global changes in gene expression, is a marker of poor survival in MPNST [77]. Normally, PRC2 transcriptionally represses several genes in the CDK pathway, including CDKN2A and the genes encoding cyclins D1 and E1, CCND1 and CCNE1 [81].…”

“…Trp53 deletion results in poorly differentiated soft tissue sarcomas [132]; however, a true EwS mouse model is yet to be developed [49]. [36,38,39], MFS [36,59], PLPS [37,66], LMS [36,37,74], CS [101], OS [116,118], EwS [130], MPNST [82] CDKN2A p16 INK4a and ARF Deletion, Mutation UPS [36,40], MFS [36,59], LMS [75], MPNST [36,[77][78][79][80]82,[133][134][135][136][137][138], CS [101], ARMS [139], OS [116,118], EwS [130] CDKN2B p15 INK4b Deletion MFS [36,59], MPNST [36,134,136] CCND1-3 Cyclin D1-3 Amplification MFS [59], LMS [75], CS [101], OS …”

The Role of Polycomb Repressive Complex in Malignant Peripheral Nerve Sheath Tumor

“…Not surprisingly, the consequences of PRC2 loss on the oncogenic signaling within the MPNST cell has become an intensive area of investigation in the NF1 research community. The current paradigm proposes a combination of H3K27me3 loss and de-repression of PRC2 target genes along with other consequential epigenetic alterations in the chromatin landscape promoting oncogenesis [108]. However, it remains unclear exactly what arethe MPNST specific PRC2 target genes that are de-repressed as the malignant transformation takes place.…”

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

“…These include molecular variants of the NF1 tumor suppressor gene that are present in all NF1 patients, and in a majority of sporadic and radiation-induced MPNSTs (2,3). Other ancillary, yet essential, cancer-driving genetic aberrations include loss of the genes CDKN2A, TP53, RB, or PTEN, or the genes encoding the PRC2 components SUZ12 or EED, and amplification of PDGFRA, EGFR, or MET (4,5). In addition, recent studies have shown that activation of multiple signaling pathways, including the PI3K/AKT/mTOR, RAS/RAF-MEK-ERK, Wnt/β-catenin, and HIPPO-YAP/TAZ pathways, and other less ubiquitous molecular alterations involving aurora kinases and transcription factors (TFs) such as SOX9, also contribute to MPNST pathogenesis (1,3,6).…”