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 volume 8, Article number: 178 (2020)
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) . 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) . In one case, molecular analyses failed to reveal any alteration of BCOR . The cIMPACT-NOW update 6 recommends the new terminology of CNS tumor with BCOR ITD to designate this entity . 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 . 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).
Interestingly, this same fusion was previously reported in gliomas  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) . 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) . 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.
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 . 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.
This study was approved by the GHU Paris Psychiatrie Neurosciences, Sainte-Anne Hospital’s local ethic committee.
The authors declare that they have no conflicts of interest directly related to the topic of this article.
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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