The EP300:BCOR fusion extends the genetic alteration spectrum defining the new tumoral entity of "CNS tumors with BCOR internal tandem duplication".
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ABSTRACT:
SUBMITTER: Tauziede-Espariat A
PROVIDER: S-EPMC7607816 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
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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".
Tauziède-Espariat Arnault A Pierron Gaëlle G Siegfried Aurore A Guillemot Delphine D Uro-Coste Emmanuelle E Nicaise Yvan Y Castel David D Catalaa Isabelle I Larrieu-Ciron Delphine D Chaynes Patrick P de Barros Amaury A Nicolau Julien J Gareton Albane A Lechapt Emmanuèle E Chrétien Fabrice F Bourdeaut Franck F Doz François F Bouchoucha Yassine Y Grill Jacques J Beccaria Kévin K Boddaert Nathalie N Saffroy Raphaël R Pagès Mélanie M Varlet Pascale P
Acta neuropathologica communications 20201102 1
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Project description:The Central Nervous System (CNS) tumor with BCOR internal tandem duplication (ITD) has recently been added as a novel embryonal histomolecular tumor type to the 2021 World Health Organization (WHO) Classification of CNS Tumors. In addition, other CNS tumors harboring a BCOR/BCORL1 fusion, which are defined by a distinct DNA-methylation profile, have been recently identified in the literature but clinical, radiological and histopathological data remain scarce. Herein, we present two adult cases of CNS tumors with EP300::BCOR fusion. These two cases presented radiological, histopathological, and immunohistochemical homologies with CNS tumors having BCOR ITD in children. To compare these tumors with different BCOR alterations, we performed a literature review with a meta-analysis. CNS tumors with EP300::BCOR fusion seem to be distinct from their BCOR ITD counterparts in terms of age, location, progression-free survival, tumor growth pattern, and immunopositivity for the BCOR protein. CNS tumors from the EP300::BCOR fusion methylation class in adults may be added to the future WHO classification.
| S-EPMC9926824 | biostudies-literature
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| S-EPMC11862909 | biostudies-literature
Project description:Clear cell sarcoma of the kidney (CCSK) and primitive myxoid mesenchymal tumour of infancy (PMMTI) are paediatric sarcomas that most commonly harbour internal tandem duplications (ITDs) of exon 15 of the BCOR gene, in the range of 87-114 base pairs (bp). Some cases, instead, have BCOR-CCNB3 or YWHAE-NUTM2 gene fusions. About 10% of cases lack any of these genetic alterations when tested by standard methods. Two cases of CCSK and one PMMTI lacking the aforementioned mutations were analysed using Archer FusionPlex technology. Two related BCOR exon 15 RNA transcripts with ITDs of lengths 388 and 96 bp were detected in each case; only the 388 bp transcript was identified when genomic DNA was sequenced. In silico analysis of this transcript revealed acceptor and donor splice sites indicating that, at the RNA level, the 388-bp transcript was likely spliced to form the 96-bp transcript. The results were confirmed by Sanger sequencing using primers targeting the ITD breakpoint. This novel and unusually long ITD segment is difficult to identify by DNA sequencing using typical primer design strategies flanking entire duplicated segments because it exceeds the typical read lengths of most sequencing platforms as well as the usual fragment lengths obtained from formalin-fixed paraffin-embedded material. As diagnosis of CCSK and PMMTI may be challenging by morphology and immunohistochemistry alone, it is important to identify mutations in these cases. Knowledge of this novel BCOR ITD is important in relation to primer design for detection by sequencing, and using RNA versus DNA for sequencing.
| S-EPMC9353662 | biostudies-literature
Project description:Central nervous system high-grade neuroepithelial tumors with BCOR alteration (CNS HGNET-BCOR) are a recently reported rare entity, identified as a small fraction of tumors previously institutionally diagnosed as so-called CNS primitive neuroectodermal tumors. Their genetic characteristic is a somatic internal tandem duplication in the 3' end of BCOR (BCOR ITD), which has also been found in clear cell sarcomas of the kidney (CCSK) and soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and these BCOR ITD-positive tumors have been reported to share similar pathological features. In this study, we performed a clinicopathological and molecular analysis of six cases of CNS HGNET-BCOR, and compared them with their counterparts in the kidney and soft tissue. Although these tumors had histologically similar structural patterns and characteristic monotonous nuclei with fine chromatin, CNS HGNET-BCOR exhibited glial cell morphology, ependymoma-like perivascular pseudorosettes and palisading necrosis, whereas these features were not evident in CCSK or URCS/PMMTI. Immunohistochemically, diffuse staining of Olig2 with a mixture of varying degrees of intensity, and only focal staining of GFAP, S-100 protein and synaptophysin were observed in CNS HGNET-BCOR, whereas these common neuroepithelial markers were negative in CCSK and URCS/PMMTI. Therefore, although CNS HGNET-BCOR, CCSK and URCS/PMMTI may constitute a group of BCOR ITD-positive tumors, only CNS HGNET-BCOR has histological features suggestive of glial differentiation. In conclusion, we think CNS HGNET-BCOR are a certain type of neuroepithelial tumor relatively close to glioma, not CCSK or URCS/PMMTI occurring in the CNS.
| S-EPMC8028450 | biostudies-literature
Project description:Undifferentiated round cell sarcomas (URCSs) usually remained unclassified due to lack of known genetic abnormalities. Herein, we retrospectively collected 5 cases of URCSs and sought to investigate their unique clinicopathologic and molecular features for providing more accurate classification. There were 2 males and 3 females with age ranged from 7 months to 17 years. The tumors were respectively located in the sacrum, fibula, neck, perineum or groin. Microscopically, all 5 tumors were composed of small-to-medium sized cells with primitive morphology and variable cellularity, distributed within loose myxoid or collagenized fibroid stroma. These tumors lacked specific immunophenotypes and known gene rearrangements. However, the expression levels of CD99 and cyclin D1 were variable. RNA-sequencing data identified one BCOR-CCNB3 gene fusion-positive sarcoma occurring in the sacrum of a 17-year-old male patient. Whole genome sequencing analysis detected BCOR exon 15-internal tandem duplication (BCOR-ITD) in the tumor arising in the groin of one 7-month-old female infant. No specific gene abnormalities were found in the other 3 cases. Interestingly, a morphological and immunohistochemical overlap existed between BCOR-rearrangement tumor and BCOR-ITD-positive tumor, including areas with hypercellularity alternating with hypocellularity, a mixture of round cells and focal spindle cells, pale nuclear chromatin, inconspicuous nucleoli and abundant myxoid matrix, diffuse strong cyclin D1 expression, relatively strong expression of CD99 but lower than that in Ewing sarcoma, and a low Ki-67 proliferation index of about 10%. Our findings demonstrated a significant link between genetic aberration and histopathologic appearances, thus supporting the crucial role of genetic characteristics in accurate clinicopathological classification.
| S-EPMC6789234 | biostudies-literature
Project description: Not available
| S-EPMC10673683 | biostudies-literature
Project description:Genomewide DNA methylation array profiling of 37 BCOR altered tumors and 37 non-BCOR altered tumors to study the rare tumor entity of EP300::BCOR fusion in central nervous system. The raw methylation idat files and processed beta values were provided here.
2022-10-09 | GSE211156 | GEO
Project description:Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors.
| S-EPMC8070097 | biostudies-literature
Project description:High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical follow-up in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.
| S-EPMC6859193 | biostudies-literature
Project description:PurposeClear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor that is frequently difficult to distinguish among other childhood renal tumors due to its histological heterogeneity. This work evaluates genetic abnormalities carried by a series of CCSK samples by whole transcriptome sequencing (WTS), to identify molecular biomarkers that could improve the diagnostic process.MethodsWTS was performed on tumor RNA from 8 patients with CCSK. Bioinformatic analysis, with implementation of a pipeline for detection of intragenic rearrangements, was executed. Sanger sequencing and gene expression were evaluated to validate BCOR internal tandem duplication (ITD).ResultsWTS did not identify any shared SNVs, Ins/Del or fusion event. Conversely, analysis of intragenic rearrangements enabled the detection of a breakpoint within BCOR transcript recurrent in all samples. Three different in-frame ITD in exon15 of BCOR, were detected. The presence of the ITD was confirmed on tumor DNA and cDNA, and resulted in overexpression of BCOR.ConclusionsWTS coupled with specific bioinformatic analysis is able to detect rare genetic events, as intragenic rearrangements. ITD in the last exon of BCOR is recurrent in all CCSK samples analyzed, representing a valuable molecular marker to improve diagnosis of this rare childhood renal tumor.
| S-EPMC4747379 | biostudies-literature