Benign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher-order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.

中文翻译：

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NF1缺陷型皮肤和丛状神经纤维瘤的独特表观基因组改变驱动不同的MKK/p38信号传导

良性外周神经鞘瘤是 1 型神经纤维瘤病的临床标志。它们导致 NF1 的大量发病率和死亡率。皮肤 (CNF) 和丛状神经纤维瘤 (PNF) 具有几乎相同的组织学，但保持不同的生长速率和恶性转化的风险。最近的基因组或转录组分析研究无法很好地解释这种不同临床行为的原因。我们假设 CNF 和 PNF 是表观遗传上不同的肿瘤类型，由于全基因组和位点特异性甲基化事件而表现出不同的信号传导。我们使用 Illumina EPIC 850K 甲基化阵列询问了来自 NF1 受试者的 45 个 CNF 和 17 个 PNF 的甲基化谱。根据这些资料，我们确认 CNF 和 PNF 是表观遗传学上不同的肿瘤，在高阶染色质状态和特定甲基化事件上存在广泛差异，这些事件会改变参与关键生物和细胞过程的基因，例如炎症、RAS/MAPK 信号传导、肌动蛋白细胞骨架重排和催产素信号传导。基于我们对 MAP2K3 中与替代前导外显子相关的两个独立 DMR 的鉴定，我们证明了 CNF 和 PNF 之间的差异 RAS/MKK3/p38 信号传导。RAS/MKK/p38 的表观遗传强化是导致促炎信号传导和染色质构象变化的 CNF 的定义特征，而 PNF 主要通过 RAS/MEK 发出信号。肿瘤大小也与特定的 CpG 甲基化事件相关。综合起来，这些发现证实 NF1 缺乏会影响 RAS 信号转导命运的表观遗传调控，从而解释观察到的 CNF 和 PNF 临床行为的差异。这些发现的延伸是，CNF 对 RAS 靶向治疗的反应可能与 PNF 不同，从而提高了靶向 p38 介导的炎症治疗 CNF 的可能性。