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EZHIP is a specific diagnostic biomarker for posterior fossa ependymomas, group PFA and diffuse midline gliomas H3-WT with EZHIP overexpression
Acta Neuropathologica Communications ( IF 6.2 ) Pub Date : 2020-11-05 , DOI: 10.1186/s40478-020-01056-8
C Antin 1 , A Tauziède-Espariat 1 , M-A Debily 2, 3 , D Castel 2, 4 , J Grill 2, 4 , M Pagès 1 , O Ayrault 5, 6 , F Chrétien 1 , A Gareton 1 , F Andreiuolo 1 , E Lechapt 1 , P Varlet 1
Affiliation  

In the central nervous system (CNS), the loss of H3K27me3 expression constitutes the hallmark of two different tumor types: diffuse midline glioma (DMG), H3K27-mutant and posterior fossa ependymoma, group PFA (PFA-EPN). In the former, mutations in histone genes (mostly H3F3A K27M and HIST1H3B K27M), present in about 97% of DMG, inhibit the activity of the Polycomb Repressive Complex 2 (PRC2) methyltransferase [1]. However, these mutations are rare in PFA-EPN (accounting for ≈ 4% of cases) [2]. Recent molecular advances have shown that the Enhancer of Zest Homologs Inhibitory Protein (EZHIP) is overexpressed (due to gene overexpression rather than mutations of the CXorf67 gene) in the large majority of PFA-EPN, and in the remaining cases of DMG showing H3K27me3 loss but lacking histone gene (H3) mutations [1,2,3]. Indeed, this overexpression mimics the mechanism of histone gene mutations on PRC2 [4]. Usually, the current routine immunohistochemical (IHC) panel in pediatric neuropathology includes H3K27me3 and H3K27M antibodies but not EZHIP. The aim of our study was to evaluate the sensitivity and specificity of the EZHIP biomarker in a large cohort of pediatric tumors, including the most common tumor types, which arise in the brainstem and the posterior fossa.

We performed IHC for EZHIP using the CXorf67 antibody (Polyclonal; 1:75 dilution; Sigma-Aldrich; Bromma, Sweden) on 3 µm-thick sections of formalin-fixed, paraffin-embedded tissue samples of these tumors, performed on an Omnis automate. Our study included a total of 311 cases: 298 pediatric tumors of different subtypes (gliomas, embryonal, and ependymal tumors with a morphomolecular diagnosis including DNA-methylation profiling), and 13 posterior fossa ependymomas, Group PFB (for details see Table 1). This series includes some of the tumors previously reported [1]. The IHC were performed on whole sections in 266 cases and on a TMA (tissue microarray) of 45 ependymomas as a validation cohort which included PFA (n = 37), H3K27-mutant (n = 2) and PFB (n = 6). The IHC stainings were scored by three neuropathologists (ATE, PV and EL) independently.

Table 1 Immunohistochemical results of EZHIP in our series
Full size table

The IHC results (including the validation cohort) are detailed in Table 1. A strong and diffuse EZHIP nuclear staining (> 90% of immunopositive tumor cells) was observed in all DMG, H3-wildtype with EZHIP overexpression (n = 13) (Fig. 1A–C) and all PFA-EPN (n = 47) (Fig. 2A–C and Additional file 1: Figure S1), except the two EPN, H3K27-mutants (Fig. 2G–I). The majority of germinomas exhibited a strong nuclear immunostaining (94%, 29/31 cases) associated with a loss of H3K27me3 trimethylation (Fig. 1G–I and Additional file 2: Figure S2). In all other diagnoses, tumor cells were immunonegative except for two cases: one atypical teratoid/rhabdoid tumor (AT/RT) belonging to the MYC methylation class and one medulloblastoma, WNT-activated. These two cases exhibited only focal expression (< 1% of immunopositive tumor cells) (data not shown). This low protein expression of EZHIP was correlated with a normal level of CXorf67 gene expression at the mRNA level. Thus, the specificity and the sensitivity of the IHC were evaluated as 99% and 98% respectively.

Fig. 1
figure1

EZHIP expression in diffuse midline gliomas. A distinct H3K27me3 loss (A, magnification, ×400) in one case of diffuse midline glioma with EZHIP overexpression, without expression of H3K27-mutant protein (B, magnification, ×400) and with strong positive EZHIP expression (C, magnification, ×400). A case of diffuse midline glioma, H3K27-mutant with a loss of expression of H3K27me3 (D, magnification, ×400), nuclear expression of H3K27-mutant protein (E, magnification, ×400), and without expression of EZHIP (F, magnification, ×400). DMG diffuse midline glioma, WT wildtype. Black scale bars represent 50 μm

Full size image
Fig. 2
figure2

EZHIP expression in ependymomas. The first line shows immunohistochemical analyses of a case of PFA-EPN exhibiting a loss of H3K27me3 (A, magnification, ×170), no H3K27-mutant protein (B, magnification, ×170) and an EZHIP overexpression with a strong and diffuse nuclear staining (C, magnification, ×170). The second line represents a case of PFB-EPN with, as expected, no loss of H3K27me3 expression (D, magnification, ×170), no H3K27-mutant protein expression (E, magnification, ×170), and negative EZHIP immunostaining (F, magnification, ×170). The last case (line 3) corresponds to a variant of PFA-EPN with H3K27-mutation exhibiting an H3K27me3 loss (G, magnification, ×170), a strong positive staining for H3K27-mutant protein (H, magnification, ×170) and no EZHIP expression (I, magnification, ×170). Black scale bars represent 250 μm

Full size image

This work constitutes the first study of the sensitivity/specificity of EZHIP immunoexpression in a large cohort of CNS tumors. Our results highlighted that nuclear EZHIP expression must be diffuse and strong to be interpreted as overexpressed. Thus, EZHIP IHC constitutes a fast, low-cost and conservative tissue-consuming method to detect CXorf67 overexpression, suitable for small samples (particularly in brainstem biopsies), but also in samples that contain few tumor cells. The IHC may also help to evaluate the quality of resection (surgical limits). Indeed, a nuclear immunopositivity is easier to interpret than the loss of H3K27me3. Our work highlighted the robust specificity of EZHIP staining in all PF ependymomas, group PFA and in all DMG, H3-wildtype with EZHIP overexpression, ruling out the main differential diagnoses encountered in children in the brainstem and in the posterior fossa (Table 1). All germinomas except two exhibited a strong positivity for EZHIP concomitant with a loss of H3K27me3 as published previously [2, 7]. Concerning HGG, MYCN-amplified none of our 9 cases (confirmed by DNA-methylation profiling and previously reported [5, 6]), were immunopositive, contrarily to a previous study which reported an expression of EZHIP in 13% of cases [1]. Moreover, this biomarker may represent a diagnostic but also a prognostic tool. Indeed, PFA-EPN were associated with a poorer prognosis than PFB-EPN, and patients with DMG overexpressing EZHIP presented a better overall survival compared to DMG, H3K27-mutant [1].

To conclude, we demonstrated that EZHIP IHC is a highly specific and sensitive biomarker for identifying PFA-EPN and DMG, H3-wildtype, with EZHIP overexpression, and should be part of the neuropathologist’s routine panel of antibodies.

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    Castel D, Kergrohen T, Tauziède-Espariat A, Mackay A, Ghermaoui S, Lechapt E et al (2020) Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation. Acta Neuropathol (Berl) 139:1109–1113

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    Pajtler KW, Wen J, Sill M, Lin T, Orisme W, Tang B et al (2018) Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol (Berl) 136:211–226

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    Pratt D, Quezado M, Abdullaev Z, Hawes D, Yang F, Garton HJL et al (2020) Diffuse intrinsic pontine glioma-like tumor with EZHIP expression and molecular features of PFA ependymoma. Acta Neuropathol Commun 8:37

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    Hübner J-M, Müller T, Papageorgiou DN, Mauermann M, Krijgsveld J, Russell RB et al (2019) EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma. Neuro-Oncol 21:878–889

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    Tauziède-Espariat A, Debily M-A, Castel D, Grill J, Puget S, Sabel M et al (2019) An integrative radiological, histopathological and molecular analysis of pediatric pontine histone-wildtype glioma with MYCN amplification (HGG-MYCN). Acta Neuropathol Commun 7:87

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    Tauziède-Espariat A, Debily M-A, Castel D, Grill J, Puget S, Roux A et al (2020) The pediatric supratentorial MYCN-amplified high-grade gliomas methylation class presents the same radiological, histopathological and molecular features as their pontine counterparts. Acta Neuropathol Commun 8:104

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    Ragazzini R, Pérez-Palacios R, Baymaz IH, Diop S, Ancelin K, Zielinski D et al (2019) EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells. Nat Commun 10:3858

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MAD was supported by a grant from the Kick Cancer/Innovative Therapies for Children with Cancer (ITCC). JG was supported by a grant from Imagine for Margo for the BIOMEDE trial. DC was supported by a grant from L’Etoile de Martin and the Fondation Carrefour “Les Boucles du Coeur”.

Affiliations

  1. Department of Neuropathology, GHU Paris-Neurosciences, Sainte-Anne Hospital, 1, rue Cabanis, 75014, Paris, France

    C. Antin, A. Tauziède-Espariat, M. Pagès, F. Chrétien, A. Gareton, F. Andreiuolo, E. Lechapt & P. Varlet

  2. UMR8203, Vectorologie et thérapeutiques anticancéreuses, CNRS, Gustave Roussy, Univ. Paris-Sud, Univ. Paris-Saclay, 94805, Villejuif Cedex, France

    M.-A. Debily, D. Castel & J. Grill

  3. Univ. Evry, Université Paris-Saclay, 91057, Evry Cedex, France

    M.-A. Debily

  4. Department of Pediatric Oncology, Gustave Roussy Institute, Univ. Paris-Sud, Universite Paris-Saclay, 94805, Villejuif, France

    D. Castel & J. Grill

  5. CNRS UMR, INSERM, Institut Curie, PSL Research University, 91898, Orsay, France

    O. Ayrault

  6. CNRS UMR 3347, INSERM U1021, Université Paris Sud, Université Paris-Saclay, 91898, Orsay, France

    O. Ayrault

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Additional file 1: Figure S1.

EZHIP expression in ependymomas of different grades. The first line shows immunohistochemical analyses of a case of grade 2 PFA-EPN (A, HPS magnification, 400x) exhibiting a loss of H3K27me3 (B, magnification, 400x), and an EZHIP overexpression with a strong and diffuse nuclear staining (C, magnification, 400x). The second line represents a case of grade 3 PFA-EPN with microvascular proliferation and mitoses (white arrowheads) (D, HPS magnification, 400x), with a loss of H3K27me3 expression (E, magnification, 400x), and strong and diffuse EZHIP immunopositivity (F, magnification, 400x). HPS: Hematoxylin Phloxin Saffron. Black scale bars represent 50 μm.

Additional file 2: Figure S2.

EZHIP expression in germinomas. A case of germinoma with H3K27me3 loss (A, magnification, 400x), no expression of H3K27-mutant protein (B, magnification, 400x), and strong and diffuse nuclear immunoexpression of EZHIP (C, magnification, 400x). Black scale bars represent 50 μm.

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Antin, C., Tauziède-Espariat, A., Debily, M. et al. EZHIP is a specific diagnostic biomarker for posterior fossa ependymomas, group PFA and diffuse midline gliomas H3-WT with EZHIP overexpression. acta neuropathol commun 8, 183 (2020). https://doi.org/10.1186/s40478-020-01056-8

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中文翻译：
EZHIP 是 EZHIP 过表达的后颅窝室管膜瘤、PFA 组和弥漫性中线胶质瘤 H3-WT 的特异性诊断生物标志物

在中枢神经系统 (CNS) 中，H3K27me3 表达的缺失构成了两种不同肿瘤类型的标志：弥漫性中线胶质瘤 (DMG)、H3K27 突变型和后颅窝室管膜瘤，PFA 组 (PFA-EPN)。在前者中，大约 97% 的 DMG 中存在组蛋白基因（主要是H3F3A K27M 和HIST1H3B K27M）的突变抑制多梳抑制复合物 2 (PRC2) 甲基转移酶的活性 [1]。然而，这些突变在 PFA-EPN 中很少见（约占病例的 4%）[2]。最近的分子进展表明，Zest 同源抑制蛋白增强剂 (EZHIP) 过度表达（由于基因过度表达而不是CXorf67基因）在绝大多数 PFA-EPN 中，在其余的 DMG 病例中，显示 H3K27me3 丢失但缺乏组蛋白基因 (H3) 突变 [1,2,3]。事实上，这种过度表达模仿了 PRC2 组蛋白基因突变的机制 [4]。通常，目前儿科神经病理学中的常规免疫组织化学 (IHC) 面板包括 H3K27me3 和 H3K27M 抗体，但不包括 EZHIP。我们研究的目的是评估 EZHIP 生物标志物在大量儿科肿瘤中的敏感性和特异性，包括最常见的肿瘤类型，它们出现在脑干和后颅窝。

我们使用 CXorf67 抗体（多克隆；1:75 稀释；Sigma-Aldrich；Bromma，瑞典）对这些肿瘤的福尔马林固定、石蜡包埋的组织样本的 3 µm 厚切片进行了 EZHIP IHC，在 Omnis 自动化上进行. 我们的研究共包括 311 例病例：298 例不同亚型的儿科肿瘤（胶质瘤、胚胎和室管膜肿瘤，形态分子诊断包括 DNA 甲基化分析），以及 13 例后颅窝室管膜瘤，PFB 组（详见表 1）。该系列包括一些先前报道的肿瘤 [1]。IHC 在 266 个病例的整个切片和 45 个室管膜瘤的 TMA（组织微阵列）上进行，作为验证队列，其中包括 PFA（n = 37）、H3K27 突变体（n = 2）和 PFB（n = 6）。IHC 染色由三位神经病理学家（ATE、PV 和 EL）独立评分。

表 1 我们系列中 EZHIP 的免疫组化结果
全尺寸表

IHC 结果（包括验证队列）在表 1 中详述。在所有 DMG、H3 野生型 EZHIP 过表达（n = 13）中观察到强且弥散的 EZHIP 核染色（> 90% 的免疫阳性肿瘤细胞）（图. 1A-C）和所有 PFA-EPN（n = 47）（图 2A-C 和附加文件 1：图 S1），除了两个 EPN，H3K27-突变体（图 2G-I）。大多数生殖细胞瘤表现出与 H3K27me3 三甲基化缺失相关的强核免疫染色（94%，29/31 例）（图 1G-I 和附加文件 2：图 S2）。在所有其他诊断中，除两种情况外，肿瘤细胞均为免疫阴性：一种属于MYC 的非典型畸胎瘤/横纹肌样瘤 (AT/RT)甲基化类和一种成神经管细胞瘤，WNT 激活。这两个病例仅表现出局灶性表达（< 1% 的免疫阳性肿瘤细胞）（数据未显示）。EZHIP 的这种低蛋白表达与mRNA 水平的正常CXorf67基因表达水平相关。因此，IHC 的特异性和敏感性分别被评估为 99% 和 98%。

图。1
图1

EZHIP 在弥漫性中线胶质瘤中的表达。一个显着的H3K27me3损失（甲，放大×400），其与EZHIP过表达漫中线神经胶质瘤中的一个情况下，无需H3K27突变蛋白的表达（乙，放大×400），并用强阳性EZHIP表达（Ç，放大倍率，× 400）。一例弥漫性中线胶质瘤，H3K27-突变，H3K27me3 表达缺失（D，放大倍数，×400），H3K27-突变蛋白核表达（E，放大倍数，×400），无 EZHIP 表达（F，放大倍数，×400）。DMG弥漫性中线胶质瘤，WT野生型。黑色比例尺代表 50 μm

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图2
图2

EZHIP 在室管膜瘤中的表达。第一行显示了 PFA-EPN 病例的免疫组织化学分析，该病例表现出 H3K27me3 缺失（A，放大倍数，×170），无 H3K27 突变蛋白（B，放大倍数，×170）和 EZHIP 过表达，具有强而弥散的核染色（C，放大倍数，×170）。第二行代表 PFB-EPN 的情况，如预期的那样，H3K27me3 表达没有丢失（D，放大倍数，×170），没有 H3K27 突变蛋白表达（E，放大倍数，×170），并且 EZHIP 免疫染色阴性（F，放大倍数，×170）。最后一个案例（第 3 行）对应于具有 H3K27 突变的 PFA-EPN 变体，表现出 H3K27me3 丢失（G，放大倍数，×170），H3K27 突变蛋白的强阳性染色（H，放大倍数，×170）并且没有 EZHIP 表达（I，放大倍数，×170）。黑色比例尺代表 250 μm

全尺寸图片

这项工作构成了对大量中枢神经系统肿瘤中 EZHIP 免疫表达的敏感性/特异性的第一项研究。我们的结果强调，核 EZHIP 表达必须是弥散和强烈的，才能被解释为过度表达。因此，EZHIP IHC 构成了一种快速、低成本和保守的组织消耗方法来检测CXorf67过表达，适用于小样本（尤其是脑干活检），但也适用于包含很少肿瘤细胞的样本。IHC 也可能有助于评估切除质量（手术限制）。事实上，核免疫阳性比 H3K27me3 的丢失更容易解释。我们的工作强调了 EZHIP 染色在所有 PF 室管膜瘤、PFA 组和所有 DMG、EZHIP 过表达的 H3 野生型中的强大特异性，排除了在儿童脑干和后颅窝中遇到的主要鉴别诊断（表 1）。除两个以外的所有生殖细胞瘤都对 EZHIP 表现出强阳性，同时伴有先前发表的 H3K27me3 的丢失 [2, 7]。关于 HGG, MYCN- 扩增我们的 9 个病例（通过 DNA 甲基化分析证实和之前报道的 [5, 6]）中没有一个是免疫阳性的，这与之前的一项研究相反，该研究报告了 13% 的病例中 EZ​​HIP 的表达 [1]。此外，这种生物标志物可能代表一种诊断工具，也代表一种预后工具。事实上，PFA-EPN 的预后比 PFB-EPN 更差，与 DMG、H3K27 突变体相比，过表达 EZHIP 的 DMG 患者的总生存期更好 [1]。

总而言之，我们证明 EZHIP IHC 是一种高度特异性和敏感的生物标志物，用于识别具有 EZHIP 过表达的 PFA-EPN 和 DMG、H3 野生型，并且应该是神经病理学家常规抗体组的一部分。

  1. 1.

    Castel D、Kergrohen T、Tauziède-Espariat A、Mackay A、Ghermaoui S、Lechapt E 等人 (2020) 过度表达 EZHIP 的组蛋白 H3 野生型 DIPG/DMG 扩展了弥漫性中线神经胶质瘤的范围，PRC2 抑制超出了 H3-K27M 突变。Acta Neuropathol (Berl) 139:1109–1113

    文章 谷歌学术

  2. 2.

    Pajtler KW、Wen J、Sill M、Lin T、Orisme W、Tang B 等（2018）后颅窝 A 组（PFA）室管膜瘤的分子异质性和 CXorf67 改变。Acta Neuropathol (Berl) 136:211–226

    CAS 文章 Google Scholar

  3. 3.

    Pratt D、Quezado M、Abdullaev Z、Hawes D、Yang F、Garton HJL 等人 (2020) 弥漫性内在性脑桥胶质瘤样肿瘤与 EZHIP 表达和 PFA 室管膜瘤的分子特征。Acta Neuropathol Commun 8:37

    文章 谷歌学术

  4. 4.

    Hübner JM、Müller T、Papageorgiou DN、Mauermann M、Krijgsveld J、Russell RB 等 (2019) EZHIP/CXorf67 模拟 K27M 突变的癌组蛋白，在侵袭性后颅窝室管膜瘤中作为 PRC2 功能的内在抑制剂发挥作用。神经肿瘤 21：878-889

    文章 谷歌学术

  5. 5.

    Tauziède-Espariat A、Debyly MA、Castel D、Grill J、Puget S、Sabel M 等人 (2019) 对具有 MYCN 扩增的小儿脑桥组蛋白野生型胶质瘤 (HGG-MYCN) 的综合放射学、组织病理学和分子分析。Acta Neuropathol Commun 7:87

    文章 谷歌学术

  6. 6.

    Tauziède-Espariat A、Debyly MA、Castel D、Grill J、Puget S、Roux A 等人 (2020) 小儿幕上 MYCN 放大的高级神经胶质瘤甲基化类具有与其桥脑对应物相同的放射学、组织病理学和分子特征。Acta Neuropathol Commun 8:104

    文章 谷歌学术

  7. 7.

    Ragazzini R、Pérez-Palacios R、Baymaz IH、Diop S、Ancelin K、Zielinski D 等人 (2019) EZHIP 限制生殖细胞中的 Polycomb Repressive Complex 2 活性。国家通讯社 10:3858

    文章 谷歌学术

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MAD 得到了 Kick Cancer/Innovative Therapies for Children with Cancer (ITCC) 的资助。JG 得到了 Imagine 为 Margo 提供的 BIOMEDE 试验赠款的支持。DC 得到了 L'Etoile de Martin 和家乐福基金会“Les Boucles du Coeur”的资助。

隶属关系

  1. 神经病理科，GHU Paris-Neurosciences, Sainte-Anne Hospital, 1, rue Cabanis, 75014, Paris, France

    C. Antin、A. Tauziède-Espariat、M. Pagès、F. Chrétien、A. Gareton、F. Andreiuolo、E. Lechapt 和 P. Varlet

  2. UMR8203，Vectorologie et thérapeutiques anticancéreuses，CNRS，Gustave Roussy，大学。巴黎南部大学 Paris-Saclay, 94805, Villejuif Cedex, 法国

    嘛。Debily, D. Castel & J. Grill

  3. 大学 Evry, Université Paris-Saclay, 91057, Evry Cedex, France

    嘛。德比利

  4. 儿科肿瘤学系，古斯塔夫鲁西研究所，大学。Paris-Sud, Universite Paris-Saclay, 94805, Villejuif, France

    D. Castel & J. Grill

  5. CNRS UMR, INSERM, Institut Curie, PSL Research University, 91898, Orsay, France

    O.Ayrault

  6. CNRS UMR 3347, INSERM U1021, Université Paris Sud, Université Paris-Saclay, 91898, Orsay, France

    O.Ayrault

作者
  1. C. Antin查看作者出版物

    您也可以在PubMed Google Scholar中搜索此作者 

  2. A. Tauziède-Espariat查看作者出版物

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  3. 嘛。Debily查看作者出版物

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  4. D. Castel查看作者出版物

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  5. J. Grill查看作者出版物

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  6. M. Pages查看作者出版物

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  7. O. Ayrault查看作者出版物

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  8. F. Chrétien查看作者出版物

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  9. A. Gareton查看作者出版物

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  10. F. Andreiuolo查看作者出版物

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  11. E. Lechapt查看作者出版物

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  12. P. Varlet查看作者出版物

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通讯作者

与 A. Tauziède-Espariat 的通信。

利益争夺

作者声明他们没有与本文主题直接相关的利益冲突。

出版商说明

Springer Nature 对已发布地图和机构附属机构中的管辖权主张保持中立。

附加文件 1：图 S1。

EZHIP在不同级别室管膜瘤中的表达。第一行显示一例 2 级 PFA-EPN（A，HPS 放大倍数，400 倍）的免疫组织化学分析，显示H3K27me3 丢失（B，放大倍数，400 倍），以及 EZHIP 过表达，具有强而弥散的核染色（C，放大倍数，400 倍）。第二行代表 3 级 PFA-EPN 病例，具有微血管增殖和有丝分裂（白色箭头）（D，HPS 放大倍数，400 倍），H3K27me3 表达缺失（E，放大倍数，400 倍），以及强且弥漫的 EZHIP 免疫阳性（F，放大倍数，400 倍）。HPS：苏木精Phloxin藏红花。黑色比例尺代表 50 μm。

附加文件 2：图 S2。

EZHIP 在生殖细胞瘤中的表达。一例具有 H3K27me3 缺失的生殖细胞瘤（A，放大倍数，400 倍），无 H3K27 突变蛋白表达（B，放大倍数，400 倍），以及 EZHIP 的强扩散核免疫表达（C，放大倍数，400 倍）。黑色比例尺代表 50 μm。

开放获取本文根据知识共享署名 4.0 国际许可证获得许可，允许以任何媒体或格式使用、共享、改编、分发和复制，只要您适当地注明原作者和来源，提供链接到知识共享许可，并指出是否进行了更改。本文中的图像或其他第三方材料包含在文章的知识共享许可中，除非在材料的信用额度中另有说明。如果文章的知识共享许可中未包含材料，并且您的预期用途未得到法律法规的允许或超出允许的用途，则您需要直接从版权所有者处获得许可。要查看此许可证的副本，请访问 http://creativecommons.org/licenses/by/4.0/。

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引用这篇文章

Antin, C., Tauziède-Espariat, A., Debily, M.等。EZHIP 是 EZHIP 过表达的后颅窝室管膜瘤、PFA 组和弥漫性中线胶质瘤 H3-WT 的特异性诊断生物标志物。神经病理学通讯 8, 183 (2020)。https://doi.org/10.1186/s40478-020-01056-8

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  • DOI : https://doi.org/10.1186/s40478-020-01056-8
更新日期：2020-11-05
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