22 results on '"Varlet, Pascale"'
Search Results
2. Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC), new name and new problems: an illustration of one case with atypical morphology and biology.
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Tauziède-Espariat, Arnault, Guida, Lelio, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Pierron, Gaëlle, Guillemot, Delphine, Masliah-Planchon, Julien, Hasty, Lauren, Métais, Alice, Chrétien, Fabrice, and Varlet, Pascale
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CLUSTER theory (Nuclear physics) ,CENTRAL nervous system tumors ,P16 gene ,BIOLOGY ,EPIGENOMICS ,BENIGN tumors - Abstract
A novel histomolecular tumor of the central nervous system (CNS), the "diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)," has recently been identified, based on a distinct DNA methylation profile and has been added to the 2021 World Health Organization Classification of CNS Tumors. This glioneuronal tumor mainly affects the supratentorial area in children and recurrently presents with a monosomy of chromosome 14. Herein, we report the case of a DNA-methylation based diagnosis of DGONC having atypical features, such as pseudo-rosettes and the absence of a chromosome 14 monosomy, thus rendering its diagnosis very challenging. Because of the wide variety of morphologies harbored by DGONC, a large range of differential diagnoses may be hypothesized from benign to malignant. Interestingly, the current case, like one previously reported, exhibited a co-expression of OLIG2, synaptophysin and SOX10, without GFAP immunopositivity. This particular immunophenotype seems to be a good indicator for a DGONC diagnosis. The classification of DGONC amongst glioneuronal or embryonal tumors is still debated. The clinical (a pediatric supratentorial tumor), morphological (from a benign oligodendroglioma-like tumor with microcalcifications and possible neuropil-like islands to a malignant embryonal tumor with a possible spongioblastic pattern), and immunohistochemical (co-expression of OLIG2 and synaptophsyin) profiles resemble CNS, neuroblastoma, FOXR2-activated and may potentially bring them together in a future classification. Further comprehensive studies are needed to conclude the cellular origin of DGONC and its prognosis. [ABSTRACT FROM AUTHOR]
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- 2024
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3. PLAG1 fusions extend the spectrum of PLAG(L)-altered CNS tumors.
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Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Dghayem, Delphine, Laprie, Anne, Lubrano, Vincent, Richard, Pomone, Gauchotte, Guillaume, Malczuk, Joséphine, Klein, Olivier, Hasty, Lauren, Métais, Alice, Chrétien, Fabrice, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Sahm, Felix, Sievers, Philipp, Varlet, Pascale, and Uro-Coste, Emmanuelle
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SALIVARY glands ,GENE amplification ,CENTRAL nervous system tumors ,TUMORS - Abstract
To conclude, we report, for the first time, two embryonal tumors with I PLAG1 i fusions sharing clinico-radiological, histopathological, immunohistochemical, and epigenetic similarities to CNS embryonal tumors with PLAG-family amplification. Central Nervous System (CNS) embryonal tumors with PLAG-family amplification have been isolated by a distinct DNA-methylation profile [[1]]. References 1 Keck M-K, Sill M, Wittmann A, Joshi P, Stichel D, Beck P. Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification. [Extracted from the article]
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- 2023
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4. A comprehensive analysis of infantile central nervous system tumors to improve distinctive criteria for infant‐type hemispheric glioma versus desmoplastic infantile ganglioglioma/astrocytoma.
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Tauziède‐Espariat, Arnault, Beccaria, Kévin, Dangouloff‐Ros, Volodia, Sievers, Philipp, Meurgey, Alexandra, Pissaloux, Daniel, Appay, Romain, Saffroy, Raphaël, Grill, Jacques, Mariet, Cassandra, Bourdeaut, Franck, Hasty, Lauren, Métais, Alice, Chrétien, Fabrice, Blauwblomme, Thomas, Puget, Stéphanie, Boddaert, Nathalie, and Varlet, Pascale
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CENTRAL nervous system tumors ,ASTROCYTOMAS ,GENE amplification ,GLIOMAS ,FLUORESCENCE in situ hybridization ,GENE fusion - Abstract
Recent epigenomic analyses have revealed the existence of a new DNA methylation class (MC) of infant‐type hemispheric glioma (IHG). Like desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA), these tumors mainly affect infants and are supratentorial. While DIG/DIA is characterized by BRAF or RAF1 alterations, IHG has been shown to have receptor tyrosine kinase (RTK) gene fusions (ALK, ROS1, NTRK1/2/3, and MET). However, in this rapidly evolving field, a more comprehensive analysis of infantile glial/glioneuronal tumors including clinical, radiological, histopathological, and molecular data is needed. Here, we retrospectively investigated data from 30 infantile glial/glioneuronal tumors, consecutively compiled from our center. They were analyzed by two experienced pediatric neuroradiologists in consensus, without former knowledge of the molecular data. We also performed a comprehensive clinical, and histopathological examination (including molecular evaluation by next‐generation sequencing, RNA sequencing, and fluorescence in situ hybridization [FISH] analyses), as well as DNA methylation profiling for the samples having sufficient material available. The integrative histopathological, genetic, and epigenetic analyses, including t‐distributed stochastic neighbor embedding (t‐SNE) analyses segregated tumors into 10 DIG/DIA (33.3%), six IHG (20.0%), three gangliogliomas (10.0%), two pleomorphic xanthoastrocytomas (6.7%), two pilocytic astrocytomas (6.7%), two supratentorial ependymomas, ZFTA fusion‐positive (6.7%), two supratentorial ependymomas, YAP1 fusion‐positive (6.7%), two embryonal tumors with PLAGL2‐family amplification (6.7%), and one diffuse low‐grade glioma, MAPK‐pathway altered. This study highlights the significant differential features, in terms of histopathology (leptomeningeal infiltration, intense desmoplasia and ganglion cells in DIG/DIA and necrosis, microvascular proliferation, and siderophages in IHG), and radiology between DIG/DIA and IHG. Moreover, these results are consistent with the literature data concerning the molecular dichotomy (BRAF/RAF1 alterations vs. RTK genes' fusions) between DIG/DIA and IHG. This study characterized histopathologically and radiologically two additional cases of the novel embryonal tumor characterized by PLAGL2 gene amplification. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Diagnostic accuracy of a minimal immunohistochemical panel in at/rt molecular subtyping, correlated to dna-methylation profiling.
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Tauziède-Espariat, Arnault, Masliah-Planchon, Julien, Andrianteranagna, Mamy, Sievers, Philipp, Sahm, Felix, von Deimling, Andreas, Hasty, Lauren, Delattre, Olivier, Beccaria, Kévin, Métais, Alice, Chrétien, Fabrice, Varlet, Pascale, and Bourdeaut, Franck
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CENTRAL nervous system tumors - Abstract
However, because a subset of AT/RT-MYC may express SOX11, IHC MYC has to be negative in the face of SOX11 positivity to suggest an AT/RT-SHH. Atypical Teratoid/Rhabdoid Tumors (AT/RT) are malignant pediatric tumors of the Central Nervous System (CNS) and are molecularly characterized by a biallelic alteration of the I SMARCB1 i (95%) or I SMARCA4 i (5%) genes [[1]]. Of note, RNA-sequencing analysis was available for five of these cases, which, consistently with IHC, all clustered with the AT/RT-MYC tumors (Fig. AT/RT, DNA-methylation profiling, TYR, SHH, MYC, Immunohistochemistry. [Extracted from the article]
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- 2023
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6. Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature.
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Sievers, Philipp, Sill, Martin, Schrimpf, Daniel, Abdullaev, Zied, Donson, Andrew M., Lake, Jessica A., Friedel, Dennis, Scheie, David, Tynninen, Olli, Rauramaa, Tuomas, Vepsäläinen, Kaisa L., Samuel, David, Chapman, Rebecca, Grundy, Richard G., Pajtler, Kristian W., Tauziède-Espariat, Arnault, Métais, Alice, Varlet, Pascale, Snuderl, Matija, and Jacques, Thomas S.
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GENE fusion ,DNA methylation ,CENTRAL nervous system tumors ,NEUROECTODERMAL tumors ,CENTRAL nervous system injuries ,RNA sequencing - Abstract
Pediatric neoplasms in the central nervous system (CNS) show extensive clinical and molecular heterogeneity and are fundamentally different from those occurring in adults. Molecular genetic testing contributes to accurate diagnosis and enables an optimal clinical management of affected children. Here, we investigated a rare, molecularly distinct type of pediatric high-grade neuroepithelial tumor (n = 18), that was identified through unsupervised visualization of genome-wide DNA methylation array data, together with copy number profiling, targeted next-generation DNA sequencing, and RNA transcriptome sequencing. DNA and/or RNA sequencing revealed recurrent fusions involving the capicua transcriptional repressor (CIC) gene in 10/10 tumor samples analyzed, with the most common fusion being CIC::LEUTX (n = 9). In addition, a CIC::NUTM1 fusion was detected in one of the tumors. Apart from the detected fusion events, no additional oncogenic alteration was identified in these tumors. The histopathological review demonstrated a morphologically heterogeneous group of high-grade neuroepithelial tumors with positive immunostaining for markers of glial differentiation in combination with weak and focal expression of synaptophysin, CD56 and CD99. All tumors were located in the supratentorial compartment, occurred during childhood (median age 8.5 years) and typically showed early relapses. In summary, we expand the spectrum of pediatric-type tumors of the CNS by reporting a previously uncharacterized group of rare high-grade neuroepithelial tumors that share a common DNA methylation signature and recurrent gene fusions involving the transcriptional repressor CIC. Downstream functional consequences of the fusion protein CIC::LEUTX and potential therapeutic implications need to be further investigated. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Mesenchymal non-meningothelial tumors of the central nervous system: a literature review and diagnostic update of novelties and emerging entities.
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Tauziède-Espariat, Arnault, Hasty, Lauren, Métais, Alice, and Varlet, Pascale
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CENTRAL nervous system tumors ,SOFT tissue tumors ,LITERATURE reviews ,CENTRAL nervous system ,INTRACRANIAL tumors - Abstract
The fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System (CNS) now includes mesenchymal tumors that occur uniquely or frequently in the CNS. Moreover, this version has aligned the terminology of mesenchymal tumors with their soft tissue counterparts. New tumor types have been added, such as the "intracranial mesenchymal tumor, FET-CREB fusion-positive", the "CIC-rearranged sarcoma", and the "Primary intracranial sarcoma, DICER1-mutant". Other entities (such as rhabdomyosarcoma) have remained in the current WHO classification because these tumor types may present specificities in the CNS as compared to their soft tissue counterparts. Based on an extensive literature review, herein, we will discuss these newly recognized entities in terms of clinical observation, radiology, histopathology, genetics and outcome, and consider strategies for an accurate diagnosis. In light of this literature analysis, we will also introduce some potentially novel tumor types. [ABSTRACT FROM AUTHOR]
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- 2023
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8. NF2 and ZFTA evaluation in the diagnostic algorithm of pediatric posterior fossa ependymoma with H3K27ME3 retained expression.
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Tauziède-Espariat, Arnault, Ajlil, Yassine, Debily, Marie-Anne, Castel, David, Grill, Jacques, Puget, Stéphanie, Hasty, Lauren, Chrétien, Fabrice, Métais, Alice, Dangouloff-Ros, Volodia, Boddaert, Nathalie, and Varlet, Pascale
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EPENDYMOMA ,CENTRAL nervous system tumors ,GADOLINIUM - Abstract
According to our results, it may be recommended to perform L1CAM and NF B immunohistochemistry and to search for clinical and radiological criteria for NF2 before performing DNA-methylation profiling for the differential diagnosis of pediatric PFB ependymoma. 1) segregated tumors into: 10 PFB (66.7%, with an enrichment of subclass 4 as previously reported [[1]]), two ependymomas, I ZFTA- i fusion positive (13.3%), and two NF2-associated spinal ependymomas (13.3%). Radiological and histomolecular features of reclassified posterior fossa ependymomas as spinal ependymomas Case 12 (A - E): A - C IRM in a NF2 patient showing bilateral vestibular schwannomas, multiple meningiomas (B, C) and a median intra-parenchymal mass with high contrast enhancement in the bulbo-medullary junction. [Extracted from the article]
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- 2023
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9. Pediatric high-grade glioma MYCN is frequently associated with Li-Fraumeni syndrome.
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Guerrini-Rousseau, Léa, Tauziède-Espariat, Arnault, Castel, David, Rouleau, Etienne, Sievers, Philipp, Saffroy, Raphaël, Beccaria, Kévin, Blauwblomme, Thomas, Hasty, Lauren, Bourdeaut, Franck, Grill, Jacques, Varlet, Pascale, and Debily, Marie-Anne
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LI-Fraumeni syndrome ,GLIOMAS ,CENTRAL nervous system tumors ,MEDICAL care - Abstract
Léa Guerrini-Rousseau and Arnault Tauziède-Espariat have contributed equally to this work In the current World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS), pediatric high-grade gliomas (HGGs), I IDH- i and histone H3 I - i wildtype (WT) are divided into three molecular subtypes: RTK1, RTK2 and MYCN [[2]]. LFS cases do not seem to form a distinct subcluster in the DNA-methylation based classification of CNS tumors compared to those without a I TP53 i germline mutation. [Extracted from the article]
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- 2023
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10. Disseminated diffuse midline gliomas, H3K27-altered mimicking diffuse leptomeningeal glioneuronal tumors: a diagnostical challenge!
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Tauziède-Espariat, Arnault, Siegfried, Aurore, Uro-Coste, Emmanuelle, Nicaise, Yvan, Castel, David, Sevely, Annick, Gambart, Marion, Boetto, Sergio, Hasty, Lauren, Métais, Alice, Chrétien, Fabrice, Benzakoun, Joseph, Puget, Stéphanie, Grill, Jacques, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Ebrahimi, Azadeh, and Varlet, Pascale
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GLIOMAS ,CENTRAL nervous system tumors ,TUMORS ,PLANT chromosomes - Abstract
1:CAS:528:DC%2BC1cXpsV2hu7k%3D. 10.1007/s00401-018-1865-4 6 Navarro RE, Golub D, Hill T, McQuinn MW, William C, Zagzag D. Pediatric midline H3K27M-mutant tumor with disseminated leptomeningeal disease and glioneuronal features: case report and literature review. Gliomas with concomitant mutations of H3K27M and I BRAF/FGFR1 i are supposed to be associated with a better prognosis than other DMG, H3K27-altered according to some publications [[7]]. Arguing for this hypothesis, a previously published monothalamic tumor classified as ganglioglioma, H3K27M- and I BRAF i V600E-mutant presented secondary leptomeningeal dissemination 7 years after the initial diagnosis [[10]]. [Extracted from the article]
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- 2022
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11. A novel LARGE1-AFF2 fusion expanding the molecular alterations associated with the methylation class of neuroepithelial tumors with PATZ1 fusions.
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Tauziède-Espariat, Arnault, Chotard, Guillaume, le Loarer, François, Baud, Jessica, Azmani, Rihab, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Icher-de-Bouyn, Céline, Gimbert, Edouard, Hasty, Lauren, Métais, Alice, Chrétien, Fabrice, and Varlet, Pascale
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CENTRAL nervous system tumors ,SARCOMA ,METHYLATION ,DNA methylation ,TUMOR suppressor genes - Abstract
A novel DNA methylation class of tumor within the central nervous system, the "neuroepithelial tumor (NET), PATZ1 fusion-positive" has recently been identified in the literature, characterized by EWSR1- and MN1-PATZ1 fusions. The cellular origin of this tumor type remains unknown, wavering between glioneuronal or mesenchymal (as round cell sarcomas with EWSR1-PATZ1 of the soft tissue). Because of the low number of reported cases, this tumor type will not be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System (CNS). Herein, we report one case of a CNS tumor classified by DNA methylation analysis as NET-PATZ1 but harboring a novel LARGE1-AFF2 fusion which has until now never been described in soft tissue or the CNS. We compare its clinical, histopathological, immunophenotypical, and genetic features with those previously described in NET-PATZ1. Interestingly, the current case presented histopathological (astroblastoma-like features, glioneuronal phenotype), clinical (with a favorable course), genetic (1p loss), and epigenetic (DNA-methylation profiling) similarities to previously reported cases of NET-PATZ1. Our results added data suggesting that different histomolecular tumor subtypes seem to be included within the methylation class "NET, PATZ1 fusion-positive", including non PATZ1 fusions, and that further cases are needed to better characterize them. [ABSTRACT FROM AUTHOR]
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- 2022
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12. A novel SMARCA2-CREM fusion: expanding the molecular spectrum of intracranial mesenchymal tumors beyond the FET genes.
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Tauziède-Espariat, Arnault, Pierron, Gaëlle, Guillemot, Delphine, Sievers, Philipp, Cazals-Hatem, Dominique, Faillot, Thierry, Roux, Alexandre, Benzakoun, Joseph, Bockel, Sophie, Weinbreck, Nicolas, Hasty, Lauren, Lechapt, Emmanuèle, Chrétien, Fabrice, and Varlet, Pascale
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INTRACRANIAL tumors ,CENTRAL nervous system tumors ,MOLECULAR spectra ,CELL death ,SARCOMA ,CENTRAL nervous system - Abstract
A novel histomolecular tumor of the central nervous system, the "intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive" has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological (clear cell morphology with signs of malignancy), clinical (with a dismal course with several recurrences, metastases and finally the patient's death), genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology "IMT, FET-CREB fusion-positive", and that further series of cases are needed to better characterize them. [ABSTRACT FROM AUTHOR]
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- 2021
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13. Specific and Sensitive Diagnosis of BCOR -ITD in Various Cancers by Digital PCR.
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Barets, Doriane, Appay, Romain, Heinisch, Marie, Battistella, Maxime, Bouvier, Corinne, Chotard, Guillaume, Le Loarer, François, Macagno, Nicolas, Perbet, Romain, Pissaloux, Daniel, Rousseau, Audrey, Tauziède-Espariat, Arnaud, Varlet, Pascale, Vasiljevic, Alexandre, Colin, Carole, Fina, Frédéric, and Figarella-Branger, Dominique
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CENTRAL nervous system tumors ,ARTIFICIAL chromosomes ,GENE fusion ,NUCLEOTIDE sequence ,RETICULUM cell sarcoma - Abstract
BCOR is an epigenetic regulator altered by various mechanisms including BCOR -internal tandem duplication (BCOR -ITD) in a wide range of cancers. Six different BCOR -ITD in the 3'-part of the coding sequence of exon 15 have been reported ranging from 89 to 114 bp in length. BCOR -ITD is a common genetic alteration found in clear cell sarcoma of the kidney and primitive myxoid mesenchymal tumor of infancy (PMMTI) and it characterizes a new type of central nervous system tumor: "CNS tumor with BCOR -ITD". It can also be detected in undifferentiated round cell sarcoma (URCS) and in high-grade endometrial stromal sarcoma (HGESS). Therefore, it is of utmost importance to search for this genetic alteration in these cancers with the most frequent technique being RNA-sequencing. Here, we developed a new droplet PCR assay (dPCR) to detect the six sequences characterizing BCOR -ITD. To achieve this goal, we used a single colored probe to detect both the duplicated region and the normal sequence that acts as a reference. We first generated seven synthetic DNA sequences: ITD0 (the normal sequence) and ITD1 to ITD6 (the duplicated sequences described in the literature) and then we set up the optima dPCR conditions. We validated our assay on 19 samples from a representative panel of human tumors (9 HGNET-BCOR, 5 URCS, 3 HGESS, and 2 PMMTI) in which BCOR -ITD status was known using at least one other method including RNA sequencing, RT-PCR or DNA-methylation profiling for CNS tumors. Our results showed that our technique was 100% sensitive and specific. DPCR detected BCOR -ITD in 13/19 of the cases; in the remaining 6 cases additional RNA-sequencing revealed BCOR gene fusions. To conclude, in the era of histomolecular classification of human tumors, our modified dPCR assay is of particular interest to detect BCOR -ITD since it is a robust and less expensive test that can be applied to a broad spectrum of cancers that share this alteration. [ABSTRACT FROM AUTHOR]
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- 2021
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14. Immunohistochemistry as a tool to identify ELP1-associated medulloblastoma.
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Tauziède-Espariat, Arnault, Guerrini-Rousseau, Léa, Perrier, Alexandre, Torrejon, Jacob, Bernardi, Flavia, Varlet, Pascale, Hasty, Lauren, Delattre, Olivier, Beccaria, Kévin, Métais, Alice, Ayrault, Olivier, Chrétien, Fabrice, Bourdeaut, Franck, Dufour, Christelle, and Masliah-Planchon, Julien
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MEDULLOBLASTOMA ,CENTRAL nervous system tumors ,IMMUNOHISTOCHEMISTRY - Abstract
The I ELP1 i gene encodes for the protein ELP1 which is a component of the elongator complex, a six-subunit protein complex (ELP1-6) implicated in neurogenesis [[1]]. Fourteen percent of them have been reported with bi-allelic alterations of I ELP1 i , a tumor-suppressor gene being currently the most frequent to predispose to MB [[4]]. [Extracted from the article]
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- 2022
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15. Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases.
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Appay, Romain, Pages, Mélanie, Colin, Carole, Jones, David T. W., Varlet, Pascale, and Figarella-Branger, Dominique
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CENTRAL nervous system tumors ,METHYLATION ,MOLECULAR spectra - Abstract
Diffuse leptomeningeal glioneuronal tumor (DLGNT) was introduced, for the first time, as a provisional entity in the 2016 WHO classification of central nervous system tumors. DLGNT mainly occur in children and characterized by a widespread leptomeningeal growth occasionally associated with intraspinal tumor nodules, an oligodendroglial-like cytology, glioneuronal differentiation and MAP-Kinase activation associated with either solitary 1p deletion or 1p/19q codeletion in the absence of IDH mutation. We report here two unexpected DLGNTs adult cases, characterized by a unique supratentorial circumscribed intraparenchymal tumor without leptomeningeal involvement in spite of long follow-up. In both cases, the diagnosis of DLGNT was made after DNA-methylation profiling which demonstrated that one case belonged to the DLGNT class whereas the other remained not classifiable but showed on CNV the characteristic genetic findings recorded in DLGNT. Both cases harbored 1p/19q codeletion associated with KIAA1549:BRAF fusion in one case and with BRAF V600E and PIK3CA E545A mutations, in the other. Our study enlarges the clinical and molecular spectrum of DLGNTs, and points out that the terminology of DLGNTs is not fully appropriate since some cases could have neither diffuse growth nor leptomeningeal dissemination. This suggests that DLGNTs encompass a wide spectrum of tumors that has yet to be fully clarified. [ABSTRACT FROM AUTHOR]
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- 2020
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16. Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation.
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Castel, David, Kergrohen, Thomas, Tauziède-Espariat, Arnault, Mackay, Alan, Ghermaoui, Samia, Lechapt, Emmanuèle, Pfister, Stefan M., Kramm, Christof M., Boddaert, Nathalie, Blauwblomme, Thomas, Puget, Stéphanie, Beccaria, Kévin, Jones, Chris, Jones, David T. W., Varlet, Pascale, Grill, Jacques, and Debily, Marie-Anne
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GLIOMAS ,CENTRAL nervous system tumors - Abstract
2 Molecular and clinical portrait of H3 wild-type DMG patients. a Clinicopathological and molecular annotations are provided as bars for 19 histone H3 wild-type DMG patients. Samples are arranged in columns with genes labeled along rows. b Distribution of normalized EZHIP gene expression level, in H3-K27M (green, n = 20) and H3 wild-type (grey, n = 11) DMG patients. We propose that these EZHIP/H3-WT tumors need to be considered similar to canonical DIPG/DMG, thus extending the spectrum of DMG with PRC2 inhibition beyond H3-K27M mutation. [Extracted from the article]
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- 2020
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17. Diagnostics of pediatric supratentorial RELA ependymomas: integration of information from histopathology, genetics, DNA methylation and imaging.
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Pagès, Mélanie, Pajtler, Kristian W., Puget, Stéphanie, Castel, David, Boddaert, Nathalie, Tauziède‐Espariat, Arnault, Picot, Stéphanie, Debily, Marie‐Anne, Kool, Marcel, Capper, David, Sainte‐Rose, Christian, Chrétien, Fabrice, Pfister, Stefan M., Pietsch, Torsten, Grill, Jacques, Varlet, Pascale, and Andreiuolo, Felipe
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DNA ,DNA methylation ,CENTRAL nervous system tumors ,GENETICS ,FLUORESCENCE in situ hybridization ,DNA fingerprinting - Abstract
Ependymoma with RELA fusion has been defined as a novel entity of the revised World Health Organization 2016 classification of tumors of the central nervous system (CNS), characterized by fusion transcripts of the RELA gene and consequent pathological activation of the NFkB pathway. These tumors represent the majority of supratentorial ependymomas in children. The validation of diagnostic tools to identify this clinically relevant ependymoma entity is essential. Here, we have used interphase fluorescent in situ hybridization (FISH) for C11orf95 and RELA, immunohistochemistry (IHC) for p65‐RelA and the recently developed DNA methylation‐based classification besides conventional histopathology, and compared the precision of the methods in 40 supratentorial pediatric brain tumors diagnosed as ependymomas in the past years. Reverse transcription PCR (RT‐PCR) and RNA sequencing were performed to explore discordant cases. Furthermore, we integrated imaging and clinical features as additional layers of information. The concordance between nuclear RelA expression by IHC and RELA FISH was 100%. Concordance between IHC and DNA methylation profiling, and between FISH and DNA methylation profiling was also high (96.4% and 95.2%, respectively). Thirty‐four out of 40 (85%) cases were confirmed by integrated diagnoses as ependymal tumors, including 22 RELA‐fused ependymomas (71% of ependymal tumors), two YAP1‐fused ependymomas (6%), six non‐RELA/non‐YAP1 ependymomas (18%) and four ependymal/subependymal mixed tumors (12%). Ependymal/subependymal mixed tumors had an excellent clinical outcome despite the presence of histopathological signs of malignancy, suggesting that these tumors should not be diagnosed as classic ependymomas. DNA methylation profiling helped in the differential diagnosis of RELA‐fused ependymomas. IHC and FISH, which are available in the majority of pathology laboratories, are valuable tools to identify RELA‐fused ependymomas. [ABSTRACT FROM AUTHOR]
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- 2019
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18. Evaluation of a novel antibody to define histone 3.3 G34R mutant brain tumours.
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Haque, Farhana, Varlet, Pascale, Puntonet, Julien, Storer, Lisa, Bountali, Aikaterini, Rahman, Ruman, Grill, Jacques, Carcaboso, Angel M., Jones, Chris, Layfield, Robert, and Grundy, Richard G.
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HISTONES , *GLIOMAS , *BRAIN tumors , *BASIC proteins ,CENTRAL nervous system tumors - Abstract
Missense somatic mutations affecting histone H3.1 and H3.3 proteins are now accepted as the hallmark of paediatric diffuse intrinsic pontine gliomas (DIPG), non-brain stem paediatric high grade gliomas (pHGG) as well as a subset of adult glioblastoma multiforme (GBM). Different mutations give rise to one of three amino acid substitutions at two critical positions within the histone tails, K27M, G34R/V. Several studies have highlighted gene expression and epigenetic changes associated with histone H3 mutations; however their precise roles in tumourigenesis remain incompletely understood. Determining how such amino acid substitutions in a protein affect its properties can be challenging because of difficulties in detecting and tracking mutant proteins within cells and tissues. Here we describe a strategy for the generation of antibodies to discriminate G34R and G34V mutant histone H3 proteins from their wild-type counterparts. Antibodies were validated by western blotting and immunocytochemistry, using recombinant H3.3 proteins and paediatric GBM cell lines. The H3-G34R antibody demonstrated a high degree of selectivity towards its target sequence. Accordingly, immunostaining on a cohort of 22 formalin-fixed paraffin embedded tumours with a previously known H3.3 G34R mutation status, detected successfully the corresponding mutant protein in 11/11 G34R cases. Since there was a high concordance between genotype and immunohistochemical analysis of G34R mutant tumour samples, we analysed a series of tissue microarrays (TMAs) to assess the specificity of the antibody in a range of paediatric brain tumours, and noted immunoreactivity in 2/634 cases. Importantly, we describe the generation and validation of highly specific antibodies for G34 mutations. Overall our work adds to an extremely valuable portfolio of antibodies, not only for histopathologic detection of tumour-associated mutant histone sequences, but also facilitating the study of spatial/anatomical aspects of tumour formation and the identification of downstream targets and pathways in malignant glioma progression. [ABSTRACT FROM AUTHOR]
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- 2017
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19. Clinicopathologic prognostic factors in childhood atypical teratoid and rhabdoid tumor of the central nervous system.
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Dufour, Christelle, Beaugrand, Annick, Le Deley, Marie Cécile, Bourdeaut, Franck, André, Nicolas, Leblond, Pierre, Bertozzi, Anne-Isabelle, Frappaz, Didier, Rialland, Xavier, Fouyssac, Fanny, Edan, Christine, Grill, Jacques, Quidot, Marion, and Varlet, Pascale
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TUMORS in children ,CENTRAL nervous system tumors ,CANCER prognosis ,FOLLOW-up studies (Medicine) ,HEALTH outcome assessment ,ADJUVANT treatment of cancer ,TERATOMA ,CANCER chemotherapy - Abstract
BACKGROUND: The objective of this study was to describe the clinical and pathologic features and to identify prognostic factors in patients with atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system (CNS). METHODS: Patients aged <18 years with newly diagnosed CNS AT/RT who were treated in France between 1998 and 2008 were retrospectively identified. The study included all patients who had a diagnosis of AT/RT confirmed by pathologic review, including immunostaining for INI 1, tumor protein 53 (p53), β-catenin, claudin-6, and Ki-67 and analysis for SMARCB1/hSNF5/INI1 mutation. RESULTS: Fifty-eight patients with confirmed AT/RT were eligible for the current analysis. The median age at diagnosis was 1.4 years (range, 14 days to 8.5 years). The site of the primary tumor was supratentorial in 26 patients, infratentorial in 28 patients and spinal in 4 patients. Loss of INI1 nuclear expression was observed in 49 of 50 evaluable tumors. Positive claudin-6 was observed in 37 of 42 assessed tumors and, in 12 of those tumors, the staining was strong and diffuse. Positive nuclear immunoreactivity for β-catenin was observed in 24 of 44 tumors, and P53 was overexpressed in 31 of 44 tumors. Primary adjuvant therapy included chemotherapy in 47 patients and radiotherapy in 16 patients. The median follow-up was 58 months (range, 9-125 months), and the median survival was 9 months. Multivariate analysis identified age <2 years ( P = .01), metastasis at diagnosis ( P = .03), and strong immunopositivity for claudin-6 ( P = .03) as prognostic factors for the risk of death. CONCLUSIONS: AT/RT tumors in children carry a dismal prognosis. Age <2 years, metastasis at diagnosis, and strong claudin-6 positivity appeared to be independent prognostic factors for outcome. Cancer 2012. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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20. Solitary Fibrous Tumors and Hemangiopericytomas of the Meninges: Overlapping Pathological Features and Common Prognostic Factors Suggest the Same Spectrum of Tumors.
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Bouvier, Corinne, Métellus, Philippe, de Paula, André Maues, Vasiljevic, Alexandre, Jouvet, Anne, Guyotat, Jacques, Mokhtari, Karima, Varlet, Pascale, Dufour, Henry, and Figarella-Branger, Dominique
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MENINGES ,SARCOMA ,CENTRAL nervous system tumors ,IMMUNOHISTOCHEMISTRY ,PROGNOSTIC tests ,RETROSPECTIVE studies ,TUMORS - Abstract
Meningeal solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) are distinct entities in the World Health Organization (WHO) classification of central nervous system (CNS) tumors while they belong to the same spectrum of tumors in other locations. Well-defined histological prognostic factors are also lacking for these tumors. In order to clarify the relationship between SFT and HPC and to find histological and immunohistochemical prognostic factors, we carried out a retrospective study in 89 patients. The following histological parameters were recorded: hypercellularity, collagenic areas, cytonuclear atypias, necrosis, mitotic count per 10 high-power fields, vasculo-nervous adherences defined by engulfment of vessel or nerve by the tumor, brain infiltration. We found overlapping histological and immunohistochemical features between SFT and HPC. The most relevant histological prognostic factors in the whole cohort for both progression-free survival (PFS) and overall survival (OS) in univariate analysis were hypercellularity, high mitotic count (>5 per 10 high-power fields) and necrosis. On the basis of these results, we propose a new grading scheme for these tumors which was of pronostic value for both PFS and OS in uni- and multivariate analysis. As extent of surgery was also a prognostic factor for both PFS and OS in univariate analysis, we propose that management of SFT/HPC might be based both on quality of removal and histological grade. [ABSTRACT FROM AUTHOR]
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- 2012
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21. Astrocytes Reverted to a Neural Progenitor-like State with Transforming Growth Factor Alpha Are Sensitized to Cancerous Transformation.
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Dufour, Christelle, Cadusseau, Josette, Varlet, Pascale, Surena, Anne-Laure, De Faria, Giselle P., Dias-Morais, Amelie, Auger, Nathalie, Léonard, Nadine, Daudigeos, Estelle, Dantas-Barbosa, Carmela, Grill, Jacques, Lazar, Vladimir, Dessen, Philippe, Vassal, Gilles, Prevot, Vincent, Sharif, Ariane, Chneiweiss, Herve, and Junier, Marie-Pierre
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CENTRAL nervous system tumors ,GLIOMAS ,ASTROCYTES ,EPIDERMAL growth factor ,TRANSFORMING growth factors ,PRECANCEROUS conditions - Abstract
Abstract Gliomas, the most frequent primitive central nervous system tumors, have been suggested to originate from astro- cytes or from neural progenitors/stem cells. However, the precise identity of the cells at the origin of gliomas remains a matter of debate because no pre-neoplastic state has been yet identified. Transforming growth factor (TGF)-a, an epidermal growth factor family member, is frequently overexpressed in the early stages of glioma progression. We previously demonstrated that prolonged exposure of astrocytes to TGF-a is sufficient to trigger their reversion to a neural progenitor-like state. To determine whether TGF-a dedifferentiating effects are associated with cancerous transforming effects, we grafted intracere- brally dedifferentiated astrocytes. We show that these cells had the same cytogenomic profile as astrocytes, survived in vivo, and did not give birth to tumors. When astrocytes dedifferentiated with TGF-a were submitted to oncogenic stress using gamma irradiation, they acquired cancerous properties: they were immortalized, showed cytogenomic abnormalities, and formed high-grade glioma-like tumors after brain grafting. In contrast, irradiation did not modify the lifespan of astrocytes cultivated in serum-free medium. Addition of TGF-a after irradiation did not promote their transformation but decreased their lifespan. These results demonstrate that reversion of mature astrocytes to an embryonic state without genomic manipulation is sufficient to sensitize them to oncogenic stress. Stem Cells 2009:27:2373-2382 [ABSTRACT FROM AUTHOR]
- Published
- 2009
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22. The Implementation of DNA Methylation Profiling into a Multistep Diagnostic Process in Pediatric Neuropathology: A 2-Year Real-World Experience by the French Neuropathology Network.
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Pages, Melanie, Uro-Coste, Emmanuelle, Colin, Carole, Meyronet, David, Gauchotte, Guillaume, Maurage, Claude-Alain, Rousseau, Audrey, Godfraind, Catherine, Mokhtari, Karima, Silva, Karen, Figarella-Branger, Dominique, Varlet, Pascale, and Giangaspero, Felice
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DIAGNOSIS of tumors in children ,NEUROLOGISTS ,CENTRAL nervous system tumors ,UNCERTAINTY ,MOLECULAR pathology ,DNA methylation ,TUMORS in children ,GENE expression profiling ,DESCRIPTIVE statistics ,LONGITUDINAL method ,CHILDREN - Abstract
Simple Summary: Supported by the "easy-to-use" and free DKFZ central nervous system (CNS) tumor classification web tool, DNA methylation profiling is a method changing the routine diagnostic practice in neuro-oncology. This work depicts a real-world practice experience by the French neuropathology network of incorporating DNA methylation profiling into the diagnostic process of challenging pediatric CNS tumors. After two rounds of histopathological review by neuropathology experts—including morphology, neuroimaging, immunohistochemistry, panel sequencing and FISH—62 tumors still presenting diagnostic uncertainty were selected for DNA methylation profiling. Using the DKFZ "classifier" and combining all additional information obtained from DNA methylation array, we observed significant diagnostic refinements and amendments. DNA methylation was successful in a significant number of cases (71%) despite the complex specificities of the cohort. Our study evaluates how DNA methylation testing would impact diagnosis and presents illustrative and representative cases. DNA methylation profiling has recently emerged as a powerful tool to help establish diagnosis in neuro-oncology. Here we present our national diagnostic strategy as the French neuropathology network (RENOCLIP-LOC) and our current approach of integrating DNA methylation profiling into our multistep diagnostic process for challenging pediatric CNS tumors. The tumors with diagnostic uncertainty were prospectively selected for DNA methylation after two rounds of review by neuropathology experts. We first integrated the classifier score into the histopathological findings. Subsequent analyses using t-SNE (t-Distributed Stochastic Neighbor Embedding) representation were performed. An additional step consisted of analyzing copy-number variation data (CNV). Finally, we combined all data to establish diagnoses and evaluated the impact of DNA methylation profiling on diagnostic and grading changes that would affect patient management. Over two years, 62 pediatric tumors were profiled. (1) Integrating the classifier score to the histopathological findings impacted the diagnosis in 33 cases (53%). (2) t-SNE analysis provided arguments for diagnosis in 26/35 cases with calibrated scores <0.84 (74.3%). (3) CNV investigations also evidenced alterations used for diagnosis and prognostication. (4) A diagnosis was finally established for 44 tumors (71%). Our results support the use of DNA methylation for challenging pediatric tumors. We demonstrated how additional methylation-based analyses complement the classifier score to support conventional histopathological diagnosis. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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