VGLL融合基因定义了一种新的脑实质内中枢神经系统神经鞘瘤。

VGLL fusions define a new class of intraparenchymal central nervous system schwannoma.

作者信息

Schmid Simone, Mirchia Kanish, Tietze Anna, Liu Ilon, Siewert Christin, Nückles Jakob, Schittenhelm Jens, Behling Felix, Snuderl Matija, Hartmann Christian, Brandner Sebastian, Paine Simon M L, Korshunov Andrey, Hasselblatt Martin, Coras Roland, Epari Sridhar, Stadelmann Christine, Zechel Sabrina, Simon Michèle, Wilson Yelena, Gianno Francesca, Lucas Calixto-Hope G, Zherebitskiy Viktor, Kaimaktchiev Vassil B, Robinson Lorraina, Aldape Kenneth, Hoving Eelco W, Tops Bastiaan B J, Perera Ashwyn Augustine, Göller Pauline, Hernáiz Driever Pablo, Wesseling Pieter, Koch Arend, Perry Arie, Sahm Felix, Jones David T W, Capper David

机构信息

German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institut für Neuropathologie, Berlin, Germany.

出版信息

Neuro Oncol. 2025 May 15;27(4):1031-1045. doi: 10.1093/neuonc/noae269.

DOI:10.1093/neuonc/noae269

PMID:39713960

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12083230/

Abstract

BACKGROUND

Intracerebral schwannomas are rare tumors resembling their peripheral nerve sheath counterparts but localized in the central nervous system (CNS). They are not classified as a separate tumor type in the 2021 World Health Organization classification. This study aimed to compile and characterize these rare neoplasms morphologically and molecularly.

METHODS

We analyzed 20 tumor samples by histology, RNA next-generation sequencing, DNA-methylation profiling, copy number analyses, and single-nucleus RNA sequencing (snRNA-seq). Clinical data, including age, sex, and disease progression, were collected. Magnetic resonance imaging (MRI) series were included when available.

RESULTS

All cases with tissue available for histology review (n = 13) were morphologically consistent with intracerebral schwannoma, but differed in their extent of glial fibrillary acidic protein staining. All (n = 20) shared DNA-methylation profiles distinct from other CNS tumors, as well as from Vestigial-like family (VGLL)-altered peripheral nerve sheath tumors. Most cases (n = 14/17) harbored fusions of either Vestigial-like family member 3 (VGLL3) or Vestigial-like Family member 1 (VGLL1) (CHD7::VGLL3 [n = 9/17] and EWSR1::VGLL1 [n = 5/17]). In 2 cases, the presence of a VGLL3 fusion was also confirmed by copy number analyses (n = 2/17). MRI (n = 4) showed well-defined, nodular tumors with strong, homogeneous enhancement and no diffusion restriction. Tumors were located throughout the neuroaxis (supratentorial [n = 15], infratentorial [n = 4], and spinal [n = 1]). snRNA-seq of a VGLL1-fused tumor indicated VGLL1 upregulation in 28.6% of tumor cells (n = 1). During a median follow-up of 1.8 years (range 3 months-9 years), none of the tumors recurred (n = 10).

CONCLUSIONS

We identify and define a new benign tumor class, designated VGLL-altered intraparenchymal CNS schwannomas. These tumors feature VGLL alterations and a specific DNA-methylation profile, with schwannoma-like histopathology and CNS localization, akin to previously classified intracerebral schwannomas.

摘要

背景

脑内神经鞘瘤是一种罕见肿瘤，类似于外周神经鞘瘤，但位于中枢神经系统（CNS）。在2021年世界卫生组织分类中，它们未被归类为一种单独的肿瘤类型。本研究旨在从形态学和分子水平上对这些罕见肿瘤进行汇总和特征描述。

方法

我们通过组织学、RNA二代测序、DNA甲基化分析、拷贝数分析和单核RNA测序（snRNA-seq）对20个肿瘤样本进行了分析。收集了包括年龄、性别和疾病进展在内的临床数据。如有可用的磁共振成像（MRI）系列也纳入分析。

结果

所有有组织可供组织学检查的病例（n = 13）在形态上均与脑内神经鞘瘤一致，但胶质纤维酸性蛋白染色程度有所不同。所有病例（n = 20）的DNA甲基化谱均不同于其他中枢神经系统肿瘤，也不同于与类 vestigial 家族（VGLL）改变相关的外周神经鞘瘤。大多数病例（n = 14/17）存在类 vestigial 家族成员3（VGLL3）或类 vestigial 家族成员1（VGLL1）的融合（CHD7::VGLL3 [n = 9/17] 和 EWSR1::VGLL1 [n = 5/17]）。在2例病例中，拷贝数分析也证实了VGLL3融合的存在（n = 2/17）。MRI（n = 4）显示肿瘤边界清晰，呈结节状，强化明显且均匀，无弥散受限。肿瘤分布于整个神经轴（幕上 [n = 15]、幕下 [n = 4] 和脊髓 [n = 1]）。对一个VGLL1融合肿瘤的snRNA-seq分析表明，28.6%的肿瘤细胞（n = 1）中VGLL1上调。在中位随访1.8年（范围3个月 - 9年）期间，无肿瘤复发（n = 10）。