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.

Figure 1.. MPNST Pathogenesis.

Neoplastic growth in the nerves of an NF-1 patient is initiated after loss of the normal NF1 allele in an SPC. The ensuing paracrine signaling recruits fibroblasts, macrophages, and mast cells to the growing tumor. These tumors are termed plexiform neurofibromas (PNs), due to their heterogeneous composition. They develop in 50% of NF-1 patients. Typically, PNs only grow through adolescence. Further tumor growth in adulthood is observed to the context of ANF and MPNSTs. Upon loss of additional tumor suppressors (p53, CDKN2A, SUZ12, EED) in an NF1 null SC or SPC, SCs can transform into MPNST. This occurs in about 10% of NF-1 patients. These tumors metastasize readily and recur frequently after removal. High grade tumors are characterized by loss of H3K27me3. This figure was created in part from Servier Medical Art.

Figure 2.. PRC2 Function and Mutations in MPNST.

(a) PRC2 consists of four core components: EED, EZH2, SUZ12 and RBBP4/7 (158). There are also several PRC2 accessory polypeptides, not be discussed here. PRC2 trimethylates lysine 27 of histone H3 (158). EED (embryonic ectoderm development) recognizes trimethylated histone H3 lysine 27 (H3K27me3), allosterically activating the enzymatic activity of the entire complex (159,160). EZH2 is the catalytic component of PRC2, trimethylating H3K27 via its SET domain (158). SUZ12 is necessary for the catalytic activity of PRC2 and may regulate PRC2 activity through interactions with noncoding RNAs (161,162). RBBP4/7 recognizes unmodified histone H3, while active chromatin marks like H3K4me3 and H3K36me3 allosterically inhibit PRC2 activity (163). Loss of function mutation frequencies of PRC2 components in MPNST are denoted in red. (b) Publicly available data on PRC2 mutations in MPNSTs (cbioportal.org). Mutations in SUZ12 and EED occurred in 11 of 15 samples. Mutations in these two PRC2 core components are mutually exclusive (p = 0.042).

Figure 3.. H3K27me3 Staining in MPNST.

MPNSTs frequently exhibit global loss of H3K27me3. (a,b) Immunohistochemical staining for H3K27me3 in MPNST tissue sections. Cells showing positive staining have been identified as inflammatory cells and endothelium (164). (c) H3K27me3 staining of granular neurons in human cerebellum, which exhibit high levels of H3K27me3, and serve as a positive control (117). Recent studies have highlighted the loss of this chromatin mark as an effective means of differentiating high grade MPNST from low grade MPNST and premalignant lesions. Images were provided by Drs. Sriram Venneti and Drew Pratt.

Figure 4.. Known Non-Canonical Roles of EZH2.

While SUZ12 or EED are mutated in approximately 85% of MPNSTs, EZH2 loss of function has not been observed. Overexpression of EZH2 has been reported in MPNSTs. EZH2 inhibition and depletion have also proven efficacious in slowing MPNST growth in preclinical models despite PRC2 already being genetically inactivated. This suggests that EZH2 may assume pathogenic functions in MPNST in the absence of other PRC2 core components. Non-canonical, pathogenic roles for EZH2 have been demonstrated in numerous other contexts. For example, overexpression of catalytically inactive EZH2 in natural killer/T-cell lymphoma conferred a growth advantage to these cells. Phosphorylated EZH2 has been shown to contribute to glioblastoma, breast cancer, and prostate cancer tumorigenicity through divergent mechanisms. The efficacy of EZH2 inhibition and depletion in slowing MPNST growth in preclinical models, as well as the clearly established non-canonical roles of EZH2 in other contexts represent an understudied avenue for potential MPNST therapies.