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CNS tumors with YWHAE:NUTM2 and KDM2B-fusions present molecular similarities to extra-CNS tumors having BCOR internal tandem duplication or alternative fusions
Acta Neuropathologica Communications volume 9, Article number: 176 (2021)
BCOR (BCL6 Corepressor) internal tandem duplication (ITD) has been implicated in a wide variety of tumors of different organs : clear cell sarcomas of the kidney (CCSK), high-grade endometrial stromal sarcomas (HGESS), undifferentiated round cell sarcomas (URCS) in the soft tissue, and tumors within the central nervous system (CNS). BCOR is part of the polycomb repressive complex 1.1 (PRC1.1), in association with the KDM2B (Lysine Demethylase 2B) protein, that mediates transcriptional repression of oncosuppressors through post-translational modifications of histones. A variable proportion of CCSK, HGESS and URCS present the YWHAE:NUTM2 fusion which is always found in mutual exclusion with the BCOR ITD. Tumors with YWHAE:NUTM2 fusions also exhibit BCOR up-regulation, reinforcing the hypothesis that these two alterations activate a common pathogenetic pathway [2, 3]. CNS tumors, isolated from a series of primitive neuroectodermal tumors by a distinct methylation profile, were initially named high-grade neuroepithelial tumors (HGNET) with BCOR alteration . Because almost all HGNET-BCOR harbored BCOR ITD and of an unknown cellular origin, the cIMPACT-NOW update 6 recommends the terminology “CNS tumor with BCOR ITD” [4,5,6]. Here, we report four CNS tumors with YWHAE:NUTM2 or KDM2B fusions, which did not cluster with HGNET-BCOR by DNA-methylation analysis, but clustered with extra-CNS sarcomas with BCOR ITD or analog fusions.
These pediatric cases included a 1-year old boy (Case 1), a 7-year old boy (Case 2), a 10-year old girl (Case 3), and a 7-year old girl (Case 4). Tumors were located in the left temporal dura-mater (Case 1), the left temporal and parietal lobes (Case 2), the right parietal and occipital lobes (Case 3), and in the pons (Case 4). Case 1 was an extra-axial mass with an intense and homogeneous enhancement, and a restricted apparent diffusion coefficient (ADC), reflecting high cellularity (Fig. 1A). Case 2 was a large and well-circumscribed solid tumor with hemorrhaging and necrosis, and a slight enhancement after contrast injection (Fig. 1E). Case 3 was a well-circumscribed polycystic tumor with an intense enhancement after contrast injection and slight hypersignal on diffusion weighted images (Fig. 1I). Case #4 was a multinodular enhancing mass in the pons with non-enhancing additional tumoral infiltration on FLAIR sequence (Fig. 1M). Whole body imaging did not evidence a spinal, leptomeningeal or extra-cranial location. Three patients were alive at the end of the follow-up (12, 11, and 179 months, respectively for Cases 1, 2, and 3), only Case 4 died postoperatively. Histopathologically, these tumors were circumscribed from the parenchyma. There was an intra-tumoral hetereogeneity: oligodendroglial-like, undifferentiated (Fig. 1B and N), or ependymal features with pseudorosettes (Fig. 1F and J). Microcysts containing a myxoid substance and calcifications were respectively observed in Cases 2 and 3. Features of malignancy were obvious with necrosis, a high mitotic count and proliferation index, and microvascular proliferation in both cases. Using immunohistochemistry, there was a preserved expression of INI1 and BRG1 and no immunoexpression of LIN28A. The expression of GFAP and Olig2 was absent in three cases and focal in the last tumor. Expression of at least one neuronal marker (NeuN and neurofilaments) was present in three cases. A BCOR immunoexpression was absent or only focally present in 3/4 cases (Fig. 1D, H and L). Analysis of the RNA-seq data identified YWHAE:NUTM2A (Case 1), KDM2B:NUTM2B (Case 2), YAP1:KDM2B (Case 3), and CHST11:KDM2B (Case 4) fusions and confirmed by two of the five different methods of detection we use (Defuse V0.6.2, StarFusion v1.2.0 (STAR v 2.5.4a), Fusion Catcher v1.00, FusionMap (Oshell toolkit v10.0.1.50) and ARRIBA v1.2.0) (Fig. 2). Using the Heidelberg DNA methylation classifier, Cases 1 and 4 were not classified and Cases 2 and 3 were classified as HGNET-BCOR (with calibrated max-scores of 0.8 and 0.2). To better characterize the potential cellular origin of these cases, we performed a t-Distributed Stochastic Neighbor Embedding plot (t-SNE) analysis including HGNET-BCOR and sarcomas with BCOR alterations (HGESS and URCS, also referred to as Small Blue Round Cell Tumours—SBRCT—in the Heidelberg database) and four soft tissue sarcomas with YWHAE:NUTM2 or KDM2B fusions from our in-house database (Fig. 3). Interestingly, our four CNS cases clustered in close vicinity with sarcomas and not HGNET-BCOR (Fig. 3).
Contrary to HGNET-BCOR, CCSK and HGESS may present either BCOR ITD or YWHAE:NUTM2A/B fusions . Here, we report four CNS tumors harboring YWHAE:NUTM2 or KDM2B fusions which differed from classical CNS tumors with BCOR ITD by clinical, radiological, immunophenotypical and molecular findings. Indeed, whereas the prognosis of HGNET-BCOR is poor , the outcome of our cases seems to be better, except for Case 4 most likely due to the tumoral pontine location. Imaging of our cases was different from those described in HGNET-BCOR such as large, solid and well-circumscribed intra-axial tumors that abut the overlying dura, with restricted diffusion and weak heterogeneous enhancement after contrast injection [6, 7]. Morphologically, all tumors were undifferentiated or arranged in small nodules of round clear cells, mimicking CCSK . However, two cases presented ependymoma-like features with pseudorosettes, which have never been seen in extra-CNS tumors, contrary to CNS tumors with BCOR ITD. Immunohistochemically, only 1/4 of these tumors expressed Olig2, which is classically diffuse in CNS tumors with BCOR ITD [6, 7]. As previously described, BCOR immunoexpression was absent or focal in our cases without BCOR ITD [8, 9]. Lastly, DNA methylation clustering showed a close proximity of these cases to sarcomas with BCOR alterations. Because DNA methylation profiles are thought to represent a combination of both somatically acquired DNA methylation changes and a signature reflecting the cell of origin, and because no extra-CNS lesion was found in our cases, it is therefore reasonable to believe that they represent another tumor type than classical CNS tumors with BCOR ITD. Here, we report for the first time fusions implicating the KDM2B gene in the CNS; interestingly, only one case was previously described with a EPC1-KDM2B fusion in soft tissue . KDM2D fusions were also found in HGESS and SBRCT .
To conclude, YWHAE:NUTM2 and KDM2B-fused CNS tumors aggregate within the category of sarcomas with BCOR alterations based on their DNA methylation signatures, despite some morphological features mimicking CNS tumors with BCOR ITD. Our results suggest that CNS tumors with these types of fusions represent a CNS location of mesenchymal tumors, but more cases (with DNA methylation and expression analyses) are needed for confirmation. Current diagnostic tools involving automated classification based on DNA methylation were proved inaccurate in two of our four cases. The diagnosis of CNS tumors, BCOR ITD must therefore be ascertained by precise clustering studies.
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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.
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This study was approved by the GHU Paris Psychiatrie Neurosciences, Sainte-Anne Hospital’s local ethic committee.
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Tauziède-Espariat, A., Pierron, G., Guillemot, D. et al. CNS tumors with YWHAE:NUTM2 and KDM2B-fusions present molecular similarities to extra-CNS tumors having BCOR internal tandem duplication or alternative fusions. acta neuropathol commun 9, 176 (2021). https://doi.org/10.1186/s40478-021-01279-3