Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors—distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.

胶质神经元肿瘤是一组异质性 CNS 肿瘤，很难准确诊断。分子方法在对这些肿瘤进行分类方面非常有用——从它们的组织学模拟物中区分出精确的类别，并识别以前未被识别的肿瘤类型。使用 DNA 甲基化数据的无监督可视化方法，我们确定了一组新的肿瘤 ( n  = 20)，它们形成了一个与所有已建立的 CNS 肿瘤类型分开的集群。分子分析显示ATRX改变（16/16 例通过 DNA 测序和/或免疫组织化学）以及涉及受体酪氨酸激酶（RTK；主要是NTRK1-3）的潜在靶向基因融合) 在所有这些肿瘤中 (16/16; 100%)。此外，拷贝数分析显示55% 的病例存在CDKN2A/B的纯合缺失。组织学和免疫组织化学研究显示胶质神经元肿瘤具有同形、圆形且通常浓缩的细胞核、核周清除、高有丝分裂活性和微血管增生。肿瘤主要位于幕上 (84%)，发生在中位年龄为 19 岁的患者中。生存数据有限（n  = 18），但与其他胶质神经元肿瘤相比（中位无进展生存期 12.5 个月）指向更具侵袭性的生物学。考虑到它们的分子特征以及间变性特征，我们建议使用ATRX术语胶质神经元肿瘤改变、激酶融合和间变性特征 (GTAKA) 来描述这些肿瘤。总之，我们的研究结果突出了一种由不同 RTK 融合驱动的新型胶质神经元肿瘤，伴随着ATRX的反复改变和CDKN2A/B的纯合子缺失。NTRK 抑制等靶向方法可能是患有这些肿瘤的患者的一种治疗选择。