Pediatric Oncology Branch, Tumor Evolution and Genomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 97 Lisburn road, Belfast BT9 7AE, UK.
Genes (Basel). 2020 Mar 9;11(3):287. doi: 10.3390/genes11030287.
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 or 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.
恶性外周神经鞘瘤（MPNST）是一种侵袭性软组织肉瘤，最常发生于神经纤维瘤病 1 型（NF1）患者。尽管人们对这些肿瘤的分子机制有了越来越深入的了解，但针对这种侵袭性疾病的治疗选择仍然有限。一个潜在的关键发现是，相当一部分 MPNST 存在基因 或 中的复发性突变，这些基因是多梳抑制复合物 2（PRC2）的关键组成部分。携带这些遗传缺陷的肿瘤失去了转录抑制的标志物，即组蛋白 H3 赖氨酸残基 27 上的三甲基化（H3K27me3），并表现出失调的致癌信号。鉴于 PRC2 改变的复发，目前正在进行密集的研究工作，重点是详细描述 PRC2 缺失的表观遗传和转录组后果，以及开发针对这些病变的新治疗策略。在这篇综述文章中，我们将总结 PRC2 在 MPNST 肿瘤发生中的最新发现，包括强调 PRC2 在正常施万细胞发育和神经损伤修复中的功能，并对 PRC2 缺陷肿瘤细胞的潜在治疗弱点进行评论。
