恶性周围神经鞘瘤（MPNST）是一种侵袭性孤儿疾病，通常影响青少年或年轻人。目前的分子肿瘤生物学知识还不足以制定合理的治疗策略。我们的目的是发现具有潜在临床相关性的分子亚型。在一项欧洲多中心研究中，对来自 115 名患者的 MPNST (n = 94) 和良性神经纤维瘤 (n = 28) 的新鲜冷冻样本进行了 DNA 拷贝数和/或转录组分析。进行了无监督的转录组亚型分析，并对亚型的基因组畸变、临床病理学关联和患者生存进行了表征。MPNST 被分为主要由免疫特征和增殖过程定义的两种转录组亚型。 “免疫活性”MPNST (44%) 相对于神经纤维瘤具有持续的免疫信号，更常见的是低级别 (P = 0.01)，并且在疾病特异性生存与临床病理因素的多变量模型中具有良好的预后相关性（风险比 0.25， P = 0.003）。 “免疫缺陷”MPNST 更具攻击性，其特征是增殖特征、高基因组复杂性、异常 TP53 和 PRC2 丢失，以及几个潜在可操作靶点（EGFR、ERBB2、EZH2、KIF11、PLK1、RRM2）的高相对表达。综合基因分析表明，增殖转录组特征尤其以 DNA 拷贝数为基础，肿瘤拷贝数负担根据患者预后进一步对转录组亚型进行分层 (P < 0.01)。大约一半的 MPNST 属于“免疫缺陷型” “转录组亚型与侵袭性疾病病程、PRC2 缺失和几个潜在治疗靶点的表达相关，为分子引导干预试验提供了基本原理。非营利组织的研究资助，如致谢中所述。版权所有 © 2023 作者（ s）。由 Elsevier B.V. 出版。保留所有权利。

Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance.Fresh frozen samples of MPNSTs (n = 94) and benign neurofibromas (n = 28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival.MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. "Immune active" MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P = 0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P = 0.003). "Immune deficient" MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P < 0.01).Approximately half of MPNSTs belong to an "immune deficient" transcriptomic subtype associated with an aggressive disease course, PRC2 loss and expression of several potential therapeutic targets, providing a rationale for molecularly-guided intervention trials.Research grants from non-profit organizations, as stated in the Acknowledgements.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.