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The EP300:BCOR fusion extends the genetic alteration spectrum defining the new tumoral entity of “CNS tumors with BCOR internal tandem duplication”
Acta Neuropathologica Communications ( IF 6.2 ) Pub Date : 2020-11-02 , DOI: 10.1186/s40478-020-01064-8
Arnault Tauziède-Espariat 1 , Gaëlle Pierron 2, 3 , Aurore Siegfried 4, 5, 6 , Delphine Guillemot 3 , Emmanuelle Uro-Coste 4, 5, 6 , Yvan Nicaise 4, 5, 6 , David Castel 7 , Isabelle Catalaa 8 , Delphine Larrieu-Ciron 9, 10 , Patrick Chaynes 11 , Amaury de Barros 11 , Julien Nicolau 11 , Albane Gareton 1 , Emmanuèle Lechapt 1 , Fabrice Chrétien 1 , Franck Bourdeaut 12 , François Doz 12, 13, 14 , Yassine Bouchoucha 12 , Jacques Grill 15, 16 , Kévin Beccaria 17 , Nathalie Boddaert 14, 18 , Raphaël Saffroy 19 , Mélanie Pagès 1, 12 , Pascale Varlet 1, 14
Affiliation  

High-grade neuroepithelial tumors with the BCOR alteration (HGNET-BCOR) were isolated by a distinct methylation profile from a series of central nervous system (CNS) primitive neuroectodermal tumors (PNET) [6]. These tumors are mainly (94%, 45/48 with available molecular data) characterized by a recurrent internal tandem duplication (ITD) of the BCOR (BCL6 Corepressor) gene [1,2,3,4, 6, 9]. In rare cases, HGNET-BCOR presented a deletion of BCOR (3%, 1/48) or a mutation of the BCOR gene (3%, 1/48) [6]. In one case, molecular analyses failed to reveal any alteration of BCOR [6]. The cIMPACT-NOW update 6 recommends the new terminology of CNS tumor with BCOR ITD to designate this entity [5]. Here we report two tumors with a HGNET-BCOR methylation class (MC) but harboring a BCOR fusion with the EP300 gene (encoding the protein p300 which is an acetyltransferase histone implicated in controlling cell growth and differentiation). The aim of our work was to compare the clinical, radiological and histopathological features of these two previously published HGNET-BCOR cases with ITD.

The two observations concerned a 13-year old boy (Case #1) and a 27-year-old man (Case #2). Tumors were located in the right temporal lobe (Case #1) and in the left frontal lobe (Case #2). Central neuroradiological review revealed large and well-circumscribed tumors with a meningeal attachment but without peri-lesional edema (Figs. 1 and 2). They appeared as solid hypercellular masses with a restricted apparent diffusion coefficient (ADC) in the main part of the tumors (Figs. 1 and 2). They displayed a heterogeneous enhancement after contrast injection (Figs. 1 and 2). These imaging characteristics were similar to HGNET-BCOR radiological data descriptions such as large and well-circumscribed tumors with a meningeal attachment, no peri-lesional edema, solid and hypercellular masses and a heterogeneous enhancement after a contrast injection [9]. Histopathological review revealed that both tumors presented the same features (Figs. 1 and 2). These tumors were mainly well-circumscribed from the brain parenchyma (with few infiltrating isolated cells at the periphery of the tumors). Pseudo-rosettes and microcysts were constantly observed. These microcysts contained a myxoid substance or occasional floating neurons. One case presented calcifications. There was intra-tumoral hetereogeneity in terms of cytology, with oligo-like, embryonal, or ependymal features. Malignancy was obvious with necrosis (calcified), high mitotic count and proliferation index, and microvascular proliferation in both cases. Immunohistochemical findings are summarized in Additional file 1: Table S1, and main features are presented in Figs. 1 and 2. There was preserved expression of H3K27me3, INI1 and ATRX in the two cases, expression of GFAP was absent, whereas Olig2 was diffusely expressed in both cases. Expression of at least one neuronal marker was present in both cases. All these results were in line with the reported HGNET-BCOR with ITD (25/43 reported cases were initially diagnosed as PNET) (Table 1) [1, 2, 6, 9]. Using the Heidelberg DNA methylation classifier, our two cases were classified as HGNET-BCOR (with calibrated max-scores of 0.6 and 0.9). RNA sequencing analysis of the two cases showed a fusion between EP300 and BCOR genes, with intra exonic breakpoints (in exon 31 for EP300, and exon 4 for BCOR) (Fig. 3). None of our cases exhibited an overexpression of BCOR (Fig. 3) contrarily to 100% of reported HGNET with BCOR ITD [1, 2, 9]. The fusion EP300:BCOR causes the loss of the first 3 exons of BCOR and a part of the exon 4 encoding the Nter domain of the protein (Fig. 3). As the BCOR antibody is designed against the 300 first residues of the native protein, this epitope is missing in the resulting chimeric fusion protein and not detected by immunohistochemistry (Fig. 3).

Fig. 1
figure1

Radiological and histopathological features of #case 1. a Computed tomography scan showing a large and calcified tumor of the right temporal lobe. b T2-weighted MRI sequence reveals leptomeningeal attachment but no peri-lesional edema. c T1-weighted image, d T1-weighted image after injection of gadolinium showing a heterogeneous enhancement diffusion-weighted images. e Cerebral blood flow was low using arterial spin labeling. f Diffusion was restricted in a large part of the tumor and g apparent diffusion coefficient was low. h Compact tumor with delicate branching vessels exhibiting a chicken-wire pattern mimicking ependymoma (HPS, magnification ×200) with some calcifications (i, HPS, magnification ×200). j Microcyst formation in the tumor (HPS, magnification ×200), k containing occasional neuronal cells (arrowheads, HPS, magnification ×400). l High mitotic index (circles, HPS, magnification ×400) and m elevated MIB1 labeling index (magnification ×400). n Necrosis with calcifications, and microvascular proliferation (arrowheads, HPS, magnification ×200). o Well-circumscribed tumor on neurofilament staining (magnification ×100). p Diffuse expression of Olig2 (magnification ×400) whereas q GFAP was not expressed by tumor cells, with internal positive control (scattered astrocyte remnants designated by arrowheads) (magnification ×400). r NeuN expression by tumor cells (magnification ×400). s Intense EGFR expression (magnification ×400). Black scale bars represent 100 µm (h–j, n), and 50 μm (k–m, p–s) and 250 µm (o). HPS Hematoxylin phloxin saffron

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Fig. 2
figure2

Radiological and histopathological features of #case 2. a Coronal T2-weighted sequence showing a large tumor without peri-lesional edema in the left frontal lobe. b Axial T1-weighted image showing a left frontal mass with leptomeningeal attachment and heterogeneous enhancement after gadolinium injection. c T1-weighted image after injection of gadolinium showing a heterogeneous enhancement. d Flair sequence showing hyperintensity. e Compact tumor with delicate branching vessels exhibiting a chicken-wire pattern (HPS, magnification ×200) with oligo-like features (f, HPS, magnification ×200). g Microcyst with a sometimes myxoid background (HPS, magnification ×200) and h containing some neuronal cells (arrowheads, HPS, magnification ×400). i Area with dense cellularity and high mitotic index (arrowheads, HPS, magnification ×400) and j elevated MIB1 labeling index (magnification ×400). k Palisading necrosis (HPS, magnification ×400) and microvascular proliferation (l, HPS, magnification ×400). m The tumor is well-circumscribed from brain parenchyma, as seen on GFAP staining, without expression in the tumor (magnification ×100). (n) Diffuse expression of Olig2 (magnification ×400). o Neurofilament expression by tumor cells (magnification ×400) and p cytoplasmic expression of EMA (magnification ×400). Black scale bars represent 100 µm (e–g, k,l), and 50 μm (h,i, n–p) and 250 µm (m)

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Table 1 Comparison of clinical, histopathological and molecular data according to methylation classes and diagnoses
Full size table
Fig. 3
figure3

Fusion EP300:BCOR and correlation with immunohistochemistry. a RNAseq analysis highlights a fusion between EP300 (pink) and BCOR (blue) genes, respectively located on chr22q13.2 and chrXp11.4. As the breakpoints are intra exonic (in exon 31 for EP300, and exon 4 for BCOR), the fusion point can easily been detected by split and span reads encompassing the rearrangement with a good coverage. Localized on minus strand (inverse orientation), the DNA sequence of BCOR is switched in frame with EP300 (b Circos plot). This aberration causes the loss of the first 3 exons of BCOR and a part of the exon 4 encoding the Nter domain of the protein (dark blue). As the BCOR antibody is designed against the 300 first residues of the native protein and since this epitope is missing in the resulting chimeric fusion protein, it cannot be used for EP300-BCOR detection by IHC. c Conserved domains in the fusion protein. d Absence of expression of BCOR by immunohistochemistry with positive internal control (tumor of methylation class HGNET-BCOR with BCOR internal tandem duplication, insert) (magnification ×400). Black scale bars 50 μm (D)

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Interestingly, this same fusion was previously reported in gliomas [7] but these cases were distinct of our cases from radiology (infiltrative pattern), histopathology and immunohistochemistry (infiltrative proliferation with calcifications, composed of GFAP positive cells without expression of neuronal markers) [7]. Moreover, gliomas described by Torre et al. were in close vicinity to LGG with an MYB/MYBL1 alteration by t-Distributed Stochastic Neighbor Embedding plot (t-SNE) analysis whereas our cases were classified into the MC HGNET-BCOR and clearly clustered with HGNET-BCOR by t-SNE analysis (Fig. 4) [7]. Despite constant malignant histopathological features and a high rate of recurrences (65%, 17/26 cases), the prognosis of HGNET-BCOR with ITD remains unclear with a mortality rate of 30% (7/23 cases) [1,2,3,4, 9]. Mean/median progression-free survival (PFS) were 24.4/12.5 months and mean/median overall survival (OS) were 38.9/26.0 months in reported HGNET-BCOR with ITD [1,2,3,4, 9]. Notably, some reported cases were alive more than ten years after the initial diagnosis [2, 4]. In our cases, after total resection, patient #1 was treated by chemotherapy only and patient #2 was treated by chemotherapy and focal irradiation. Neither have presented a recurrence and are alive, 16 and 27 months after the initial diagnosis.

Fig. 4
figure4

Methylation-based t-SNE distribution. The two tumors with EP300:BCOR fusion were compared with 147 reference samples from the Heidelberg cohort belonging to the HGNET-BCOR, HGNET-MN1, LGG-MYB/MYBL, EPN-RELA, EPN-YAP methylation classes which constitute histopathological differential diagnoses. The two cases of this study are indicated as grey dots and shown by arrows. HGNET-BCOR, high-grade neuroepithelial tumors with BCOR alteration (red dots); HGNET-MN1, high-grade neuroepithelial tumors with MN1 alteration (yellow dots); LGG-MYB/MYBL1, low-grade gliomas with MYB or MYBL1 alteration (blue dots); EPN-RELA, ependymomas with RELA fusion (pink dots); EPN-YAP, ependymomas with YAP fusion (gree dots)

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To conclude, we presented for the first time two supratentorial tumors with EP300:BCOR fusion sharing clinico-radiological, histopathological, immunohistochemical, and methylome homologies with HGNET-BCOR with ITD while they did not share similarities with the previous reported gliomas harboring this same fusion. Consequently, the EP300:BCOR fusion expands the spectrum of the alterations encountered in the MC HGNET-BCOR, and therefore, the terminology “CNS tumors with BCOR ITD” seems to be too restrictive. This finding echoes the data published in small round cell sarcomas of soft tissue, which may harbor BCOR fusions (mainly with CCNB3 gene) and BCOR ITD [8]. Because the BCOR immunohistochemistry does not allow detections of HGNET-BCOR with fusion, we recommand searching for alternative alterations of the BCOR gene in the event of radiological and histopathological suspicion of this diagnosis when ITD is absent.

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We would like to thank the laboratory technicians at the GHU Paris Neuro Sainte-Anne for their assistance, as well as the Integragen platform for their technical assistance with DNA-methylation analyses and the RENOCLIP-LOC. The RENOCLIP-LOC is the clinico-pathologic network that is instrumental for the central histopathologic review supported by the Institut National du Cancer (INCa).

The authors declare that they have not received any funding.

Affiliations

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

    Arnault Tauziède-Espariat, Albane Gareton, Emmanuèle Lechapt, Fabrice Chrétien, Mélanie Pagès & Pascale Varlet

  2. INSERMU830, Institut Curie Research Center, Paris-Sciences-Lettres, Paris, France

    Gaëlle Pierron

  3. Laboratory of Somatic Genetics, Institut Curie Hospital, Paris, France

    Gaëlle Pierron & Delphine Guillemot

  4. Department of Pathology, Toulouse University Hospital, Toulouse, France

    Aurore Siegfried, Emmanuelle Uro-Coste & Yvan Nicaise

  5. INSERM U1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France

    Aurore Siegfried, Emmanuelle Uro-Coste & Yvan Nicaise

  6. Université Paul Sabatier, Toulouse III, Toulouse, France

    Aurore Siegfried, Emmanuelle Uro-Coste & Yvan Nicaise

  7. UMR8203 Vectorologie Et Therapeutiques Anticancereuses CNRS, Gustave Roussy, Univ. Paris-Sud, Universite Paris-Saclay, Villejuif, France

    David Castel

  8. Department of Radiology, Purpan University Hospital, Toulouse, France

    Isabelle Catalaa

  9. Department of Neurology, Toulouse University Hospital, Toulouse, France

    Delphine Larrieu-Ciron

  10. Department of Medical Oncology, IUCT-Oncopole, Toulouse, France

    Delphine Larrieu-Ciron

  11. Department of Neurosurgery, Toulouse University Hospital, Toulouse, France

    Patrick Chaynes, Amaury de Barros & Julien Nicolau

  12. Laboratory of Translational Research in Pediatric Oncology, SIREDO, INSERM U830, Institut Curie, Paris Sciences Lettres University, Paris, France

    Franck Bourdeaut, François Doz, Yassine Bouchoucha & Mélanie Pagès

  13. Laboratoire de Génétique Et Biologie Des Cancers, INSERM U830, Institut Curie, Paris, France

    François Doz

  14. Université de Paris, Paris, France

    François Doz, Nathalie Boddaert & Pascale Varlet

  15. U981, Molecular Predictors and New Targets in Oncology, INSERM, Gustave Roussy, Université Paris-Saclay, Villejuif, France

    Jacques Grill

  16. Département de Cancérologie de L’Enfant Et de L’Adolescent, Gustave Roussy, Université Paris-Saclay, Villejuif, France

    Jacques Grill

  17. Department of Pediatric Neurosurgery, Hôpital Universitaire Necker Enfants Malades, APHP, Université de Paris, Paris, France

    Kévin Beccaria

  18. Paediatric Radiology Department, Hôpital Necker Enfants Malades, INSERM U1163, Institut Imagine, AP-HP, University de Paris, Paris, France

    Nathalie Boddaert

  19. Department of Biochemistry and Oncogenetic, Paul Brousse Hospital, Villejuif, France

    Raphaël Saffroy

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Contributions

ATE, EUC, IC, DLC, PC, ADB, JN, JG, KB and NB compiled the MRI and clinical records; ATE, AS, EUC, YN, AG, EL, MP, FC and PV conducted the neuropathological examinations; ATE, MP, EUC, YN, JMP, GP, DG, RS and PV conducted the molecular studies; ATE, FB, FD, YB, MP, JMP and PV drafted the manuscript; all authors reviewed the manuscript.

Corresponding author

Correspondence to Arnault Tauziède-Espariat.

Ethics approval

This study was approved by the GHU Paris Psychiatrie Neurosciences, Sainte-Anne Hospital’s local ethic committee.

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The authors declare that they have no conflicts of interest directly related to the topic of this article.

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Additional file 1: Table S1.

Immunohistochemical findings of our cases of HGNET-BCOR with EP300:BCOR fusion.

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Tauziède-Espariat, A., Pierron, G., Siegfried, A. et al. The EP300:BCOR fusion extends the genetic alteration spectrum defining the new tumoral entity of “CNS tumors with BCOR internal tandem duplication”. acta neuropathol commun 8, 178 (2020). https://doi.org/10.1186/s40478-020-01064-8

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中文翻译：
在EP300：BCOR融合延伸遗传改变的频谱定义的新的肿瘤实体“CNS肿瘤与BCOR内部串联重复”

通过一系列中枢神经系统（CNS）原始神经外胚层肿瘤（PNET）的独特甲基化特征分离出具有BCOR改变的高级神经上皮肿瘤（HGNET- BCOR）[6]。这些肿瘤主要（94％，45/48有可用的分子数据）以BCOR（BCL6 Corepressor）基因的复发性内部串联重复（ITD）为特征[ 1,2,3,4,6,9 ]。在极少数情况下，HGNET- BCOR会缺失BCOR（3％，1/48）或BCOR基因突变（3％，1/48）[6]。在一种情况下，分子分析未能揭示BCOR的任何变化[6] 。cIMPACT-NOW更新6推荐使用BCOR ITD的CNS肿瘤新术语来指定该实体[5]。在这里，我们报道了两个具有HGNET- BCOR甲基化类别（MC）但具有与EP300基因融合的BCOR融合体的肿瘤（编码蛋白质p300，这是一种涉及控制细胞生长和分化的乙酰转移酶组蛋白）。我们的工作目的是比较这两个先前发表的HGNET- BCOR病例与ITD的临床，放射学和组织病理学特征。

这两个发现涉及一个13岁男孩（案例1）和一个27岁男人（案例2）。肿瘤位于右颞叶（案例1）和左额叶（案例2）。中央神经放射学检查发现大而界限分明的肿瘤伴有脑膜附着，但无病灶周围水肿（图1和2）。它们在肿瘤的主要部分表现为实性的高细胞团块，其表观扩散系数（ADC）受到限制（图1和2）。对比剂注射后，它们显示出异质性增强（图1和2）。这些成像特性类似于HGNET- BCOR放射学数据描述，例如大而界限分明的，具有脑膜附件的肿瘤，无病灶周围水肿，实性和高细胞性肿块以及造影剂注入后异质性增强[9]。组织病理学检查显示，两种肿瘤均具有相同特征（图1和2）。这些肿瘤主要是由脑实质包围的（在肿瘤周围几乎没有浸润的分离细胞）。不断观察到伪玫瑰红和微囊肿。这些微囊包含粘液样物质或偶尔漂浮的神经元。1例出现钙化。就细胞学而言，存在肿瘤内异质性，具有寡样，胚胎或室管膜功能。恶性明显，坏死（钙化），有丝分裂计数和增殖指数高，和微血管增生这两种情况。免疫组织化学结果总结在附加文件1：表S1中，主要特征显示在图1和2中。参见图1和2。在这两种情况下，H3K27me3，INI1和ATRX的表达均得以保留，在两种情况下均不表达GFAP，而Olig2则广泛表达。在两种情况下均存在至少一种神经元标记物的表达。所有这些结果均与报道的HGNET-BCOR与ITD（最初报告的25/43例病例被诊断为PNET）（表1）[1,2,6,9]。使用Heidelberg DNA甲基化分类器，我们将两个案例分类为HGNET- BCOR（校准的最大分数为0.6和0.9）。这两个案例的RNA测序分析显示，EP300和BCOR基因融合，具有内部外显子断点（EP300的第31外显子，BCOR的第4外显子）（图3）。我们的病例均未显示出BCOR的过表达（图3），与报道的使用BCOR ITD的HGNET的100％相反[ 1,2,9 ]。融合EP300：BCOR导致BCOR的前三个外显子丢失编码蛋白质Nter结构域的外显子4的一部分（图3）。由于BCOR抗体是针对天然蛋白质的300个第一个残基设计的，因此该表位在所得的嵌合融合蛋白中缺失，并且无法通过免疫组织化学检测到（图3）。

图。1
图1

＃病例1的放射学和组织病理学特征。X线计算机断层扫描显示右颞叶有大块钙化肿瘤。b T2加权MRI序列显示出软脑膜附着，但无病灶周围水肿。c T1加权图像，d injection注入后的T1加权图像显示了异质增强扩散加权图像。e使用动脉旋转标记，脑血流量低。f在大部分肿瘤中扩散受到限制，并且g表观扩散系数很低。H致密的肿瘤，分支血管细密，表现出模仿线虫病（HPS，放大倍数×200）的鸡丝状，并有一些钙化（i，HPS，放大倍数×200）。j肿瘤中微囊的形成（HPS，放大倍数×200），k偶尔包含神经元细胞（箭头，HPS，放大倍数×400）。升高有丝分裂指数（圆圈，HPS，倍率×400）及米升高MIB1标记指数（倍率×400）。n钙化坏死和微血管增生（箭头，HPS，放大倍数×200）。o神经丝染色明确界定的肿瘤（放大倍数×100）。pOlig2的扩散表达（放大倍数×400），而肿瘤细胞未表达q GFAP，内部阳性对照（箭头指示的分散的星形胶质细胞残留）（放大倍数×400）。r肿瘤细胞的NeuN表达（放大倍数×400）。■强烈的EGFR表达（放大倍数×400）。黑色比例尺代表100 µm（h – j，n），50 µm（k – m，p – s）和250 µm（o）。HPS苏木精phloxin藏红花

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图2
图2

＃病例2的放射学和组织病理学特征。冠状T2加权序列显示左额叶无肿瘤周围水肿的大肿瘤。b轴向T1加权图像显示了注射ado后左前额叶有软脑膜附着和异质增强。c注射of后的T1加权图像显示异质性增强。d Flair序列显示高强度。e致密肿瘤，分支血管细密，呈鸡丝状（HPS，放大倍数×200），具有类似寡核苷酸的特征（f，HPS，放大倍数×200）。G微囊具有有时粘液样背景（HPS，倍率×200）及ħ含有一些神经元细胞（箭头，HPS，倍率×400）。我所在区域密集细胞构成和高有丝分裂指数（箭头，HPS，倍率×400）和Ĵ升高MIB1标记指数（倍率×400）。k苍白性坏死（HPS，放大倍数×400）和微血管增生（l，HPS，放大倍数×400）。m如通过GFAP染色所见，肿瘤是脑实质的良好界限，在肿瘤中无表达（放大倍数×100）。（n）Olig2的扩散表达（放大倍数×400）。Ø肿瘤细胞表达神经丝（放大倍数×400）和EMA的p胞浆表达（放大倍数×400）。黑色刻度尺代表100 µm（e – g，k，l）以及50 µm（h，i，n – p）和250 µm（m）

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表1根据甲基化分类和诊断的临床，组织病理学和分子数据的比较
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图3
图3

融合蛋白EP300：BCOR及其与免疫组织化学的关系。一个RNA测序分析亮点EP300（粉红色）和BCOR（蓝色）的基因，分别位于chr22q13.2和chrXp11.4之间的融合。由于断点是内部外显子（对于EP300是外显子31，对于BCOR是外显子4），融合点可以很容易地通过拆分和跨度读取来检测，涵盖具有良好覆盖范围的重排。BCOR的DNA序列位于负链上（反向），与EP300（b马戏团情节）。这种畸变导致BCOR的前三个外显子和编码该蛋白Nter结构域的外显子4的一部分丢失（深蓝色）。由于BCOR抗体是针对天然蛋白质的300个第一个残基设计的，并且由于该表位在所得的嵌合融合蛋白中缺失，因此无法用于IHC进行EP300-BCOR检测。c融合蛋白中的保守结构域。d带有阳性内部对照的免疫组织化学检查不显示BCOR的表达（带有BCOR内部串联重复的甲基化类HGNET- BCOR的肿瘤，插入）（放大倍数×400）。黑色刻度尺50μm（D）

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有趣的是，以前在神经胶质瘤中也报道过这种融合[7]，但这些病例与我们的病例不同（放射学（浸润模式），组织病理学和免疫组织化学（浸润性钙化，由不表达神经元标志物的GFAP阳性细胞组成）[7]）。 ]。此外，Torre等人描述的神经胶质瘤。通过t分布随机邻居嵌入图（t-SNE）分析，MYB / MYBL1改变与LGG接近，而我们的病例被分类为MC HGNET- BCOR，并通过t-SNE分析清楚地与HGNET- BCOR聚类（图4）[7]。尽管HGNET- BCOR的恶性组织病理学特征持续不变且复发率高（65％，17/26例），尚不清楚ITD患者的死亡率为30％（7/23例）[1,2,3,4,9]。报道的带有ITD的HGNET- BCOR的平均/中位无进展生存期（PFS）为24.4 / 12.5个月，平均/中位总生存期（OS）为38.9 / 26.0个月[ 1,2,3,4,9 ]。值得注意的是，一些报告的病例在最初诊断后还活了十多年[2，4]。在我们的病例中，在完全切除后，仅对1号患者进行化学疗法治疗，对2号患者进行化学疗法和局部照射治疗。初诊后16个月和27个月均未出现复发并存活。

图4
图4

基于甲基化的t-SNE分布。将这两种具有EP300：BCOR融合的肿瘤与来自海德堡队列的147个参比样本进行了比较，这些参比属于HGNET- BCOR， HGNET-MN1，LGG- MYB / MYBL， EPN-RELA，EPN-YAP甲基化类别，这些构成了组织病理学鉴别诊断。这项研究的两个案例以灰色圆点表示，并以箭头表示。HGNET- BCOR，伴有BCOR改变的高级神经上皮肿瘤（红点）；HGNET-MN1，伴有MN1改变的高级神经上皮肿瘤（黄点）；LGG- MYB / MYBL1，伴有MYB或MYBL1的低级神经胶质瘤变更（蓝点）；EPN-RELA，与RELA融合的室间隔瘤（粉红色斑点）；EPN-YAP，带有YAP融合的室间隔瘤（格点）

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总而言之，我们首次提出了两种EP300：BCOR融合的幕上肿瘤，与HGNET - BCOR和ITD共享临床放射学，组织病理学，免疫组化和甲基化同源性，而与先前报道的具有相同融合的神经胶质瘤没有相似之处。因此，EP300：BCOR融合扩大了MC HGNET- BCOR中遇到的变化的范围，因此，术语“具有BCOR ITD的CNS肿瘤”似乎过于局限。这一发现与在软组织的小圆形细胞肉瘤中发表的数据相呼应，这些肉瘤可能带有BCOR融合蛋白（主要与CCNB3基因融合），并且BCOR ITD [8]。因为BCOR免疫组织化学不允许融合检测HGNET- BCOR，所以我们建议在没有ITD的放射学和组织病理学怀疑中寻找BCOR基因的替代改变。

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下载参考

我们要感谢GHU Paris Neuro Sainte-Anne的实验室技术人员的协助，以及Integragen平台在DNA甲基化分析和RENOCLIP-LOC方面的技术援助。RENOCLIP-LOC是临床病理网络，可用于由国家癌症研究所（INCa）支持的中央组织病理学检查。

作者宣称他们没有得到任何资助。

隶属关系

  1. 法国巴黎圣安妮医院1号GHU巴黎精神病学和神经科学科神经病理学科，75014

    ArnaultTauziède-Espariat，Albane Gareton，EmmanuèleLechapt，FabriceChrétien，MélaniePagès和Pascale Varlet

  2. INSERMU830，居里研究所研究中心，巴黎-莱特雷斯，巴黎，法国

    盖尔·皮尔龙（GaëllePierron）

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    GaëllePierron和Delphine Guillemot

  4. 法国图卢兹，图卢兹大学医院病理科

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    Aurore Siegfried，Emmanuelle Uro-Coste和Yvan Nicaise

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    Aurore Siegfried，Emmanuelle Uro-Coste和Yvan Nicaise

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    大卫·卡斯特

  8. 法国图卢兹普潘大学医院放射科

    伊莎贝尔（Isabelle Catalaa）

  9. 法国图卢兹，图卢兹大学医院神经科

    德尔菲娜·拉里乌·西龙

  10. IUCT-Oncopole，法国图卢兹，医学肿瘤学系

    德尔菲娜·拉里乌·西龙

  11. 法国图卢兹，图卢兹大学医院神经外科

    帕特里克·查恩斯（Patrick Chaynes），阿毛里·德·巴罗斯（Aaury de Barros）和朱利安·尼科劳

  12. SIREDO小儿肿瘤转化研究实验室，INSERM U830，巴黎科学莱特斯大学居里研究所，法国巴黎

    弗朗克·布尔多（Franck Bourdeaut），弗朗索瓦·多斯（FrançoisDoz），雅西娜·布ouch卡（Yassine Bouchoucha）和梅兰妮·帕吉斯（MélaniePagès）

  13. 法国巴黎居里研究所，INSERM U830，法国癌症生物学实验室

    弗朗索瓦·多兹（FrançoisDoz）

  14. 巴黎大学，法国巴黎

    FrançoisDoz，Nathalie Boddaert和Pascale Varlet

  15. U981，INSERM的分子预测因子和肿瘤新靶点，古斯塔夫·鲁西，法国巴黎萨莱大学，维勒瑞夫

    雅克烧烤

  16. 青年时期的坎特罗洛分校，古斯塔夫·鲁西，法国巴黎-萨莱大学，维勒瑞夫

    雅克烧烤

  17. 法国巴黎大学APHP内卡尔大学婴幼儿神经外科儿科神经外科系

    凯文·贝卡里亚（KévinBeccaria）

  18. 法国巴黎大学AP-HP影像研究所Inserm U1163，HôpitalNecker婴幼儿马拉德斯小儿放射科

    娜塔莉·博德特（Nathalie Boddaert）

  19. 法国维勒瑞夫Paul Brousse医院生物化学与致癌基因科

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会费

ATE，EUC，IC，DLC，PC，ADB，JN，JG，KB和NB编制了MRI和临床记录；ATE，AS，EUC，YN，AG，EL，MP，FC和PV进行了神经病理学检查；ATE，MP，EUC，YN，JMP，GP，DG，RS和PV进行了分子研究；ATE，FB，FD，YB，MP，JMP和PV起草了稿件; 所有作者都审阅了该手稿。

通讯作者

对应于ArnaultTauziède-Espariat。

道德认证

该研究得到了圣安娜医院地方伦理委员会GHU巴黎精神病学神经科学的批准。

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。

发行人须知

对于已发布地图和机构隶属关系中的管辖权主张，Springer Nature保持中立。

附加文件1：表S1。

我们的HGNET-BCOR与EP300：BCOR融合病例的免疫组织化学发现。

开放存取本文是根据知识共享署名4.0国际许可许可的，该许可允许以任何媒介或格式使用，共享，改编，分发和复制，只要您对原始作者和出处提供适当的信誉，链接到知识共享许可，并指出是否进行了更改。本文的图像或其他第三方材料包含在该文章的知识共享许可中，除非在该材料的信用栏中另有说明。如果该材料未包含在该文章的创用CC许可中，并且您的预期用途未得到法律法规的许可或超出了许可的用途，则您需要直接获得版权所有者的许可。要查看此许可证的副本，请访问http://creativecommons.org/licenses/by/4.0/。

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引用本文

Tauziède-Espariat，A.，Pierron，G.，Siegfried，A.等。在EP300：BCOR融合延伸遗传改变频谱定义“CNS肿瘤与新肿瘤实体BCOR内部串联重复”。ACTA neuropathol COMMUN 8， 178（2020）。https://doi.org/10.1186/s40478-020-01064-8

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  • DOI ：https ：//doi.org/10.1186/s40478-020-01064-8
更新日期：2020-11-03
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