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

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that can arise most frequently in patients with neurofibromatosis type 1 (NF1). Despite an increasing understanding of the molecular mechanisms that underlie these tumors, there remains limited therapeutic options for this aggressive disease. One potentially critical finding is that a significant proportion of MPNSTs exhibit recurrent mutations in the genes EED or SUZ12, which are key components of the polycomb repressive complex 2 (PRC2). Tumors harboring these genetic lesions lose the marker of transcriptional repression, trimethylation of lysine residue 27 on histone H3 (H3K27me3) and have dysregulated oncogenic signaling. Given the recurrence of PRC2 alterations, intensive research efforts are now underway with a focus on detailing the epigenetic and transcriptomic consequences of PRC2 loss as well as development of novel therapeutic strategies for targeting these lesions. In this review article, we will summarize the recent findings of PRC2 in MPNST tumorigenesis, including highlighting the functions of PRC2 in normal Schwann cell development and nerve injury repair, as well as provide commentary on the potential therapeutic vulnerabilities of a PRC2 deficient tumor cell.

Keywords: MPNST; PRC2; malignant peripheral nerve sheath tumor; neurofibromatosis; polycomb repressive complex.

Figure 1

The clinical spectrum and genetic model of nerve tumor development in neurofibromatosis type 1 (NF1). Cells shown here are Schwann cells in the dorsal ganglia root and are affected by the sequential mutations driving the malignant transformation. Green: NF1 alteration, yellow: CDKN2A alteration, and red: PRC2 alteration.

Figure 2

A compiled overview of SUZ12 and EED alterations identified in malignant peripheral nerve sheath tumors (MPNST) published to date, accounting for approximately 75% of sequenced cases. (A) A representation of single nucleotide variants (SNVs) discovered in SUZ12 thus far in MPNST sequencing studies. (B) EED SNVs identified through sequencing studies. (C) An Oncoprint map of the various mutations discovered in both SUZ12 and EED across the MPNST samples sequenced thus far. Figure generated using OncoPrinter and MutationMapper from https://www.cbioportal.org/visualize.

Figure 3

PRC2 structure and consequences of its loss in MPNST. Loss of PRC2 via EED or SUZ12 loss in MPNSTs leads to loss of tri-methylation of histone H3 lysine 27 (H3K27me3) and other potential epigenetic modifications. In addition, PRC2 loss can have a wide variety of consequences on oncogenic signaling and immune surveillance and response.