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Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature

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. Her...

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Autores principales: 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, Jacques, Thomas S., Aldape, Kenneth, Reuss, David E., Korshunov, Andrey, Wick, Wolfgang, Pfister, Stefan M., von Deimling, Andreas, Sahm, Felix, Jones, David T. W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039012/
https://www.ncbi.nlm.nih.gov/pubmed/36964296
http://dx.doi.org/10.1038/s41698-023-00372-1
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author 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
Jacques, Thomas S.
Aldape, Kenneth
Reuss, David E.
Korshunov, Andrey
Wick, Wolfgang
Pfister, Stefan M.
von Deimling, Andreas
Sahm, Felix
Jones, David T. W.
author_facet 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
Jacques, Thomas S.
Aldape, Kenneth
Reuss, David E.
Korshunov, Andrey
Wick, Wolfgang
Pfister, Stefan M.
von Deimling, Andreas
Sahm, Felix
Jones, David T. W.
author_sort Sievers, Philipp
collection PubMed
description 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.
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spelling pubmed-100390122023-03-26 Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature 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 Jacques, Thomas S. Aldape, Kenneth Reuss, David E. Korshunov, Andrey Wick, Wolfgang Pfister, Stefan M. von Deimling, Andreas Sahm, Felix Jones, David T. W. NPJ Precis Oncol Article 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. Nature Publishing Group UK 2023-03-24 /pmc/articles/PMC10039012/ /pubmed/36964296 http://dx.doi.org/10.1038/s41698-023-00372-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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
Jacques, Thomas S.
Aldape, Kenneth
Reuss, David E.
Korshunov, Andrey
Wick, Wolfgang
Pfister, Stefan M.
von Deimling, Andreas
Sahm, Felix
Jones, David T. W.
Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature
title Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature
title_full Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature
title_fullStr Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature
title_full_unstemmed Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature
title_short Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature
title_sort pediatric-type high-grade neuroepithelial tumors with cic gene fusion share a common dna methylation signature
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039012/
https://www.ncbi.nlm.nih.gov/pubmed/36964296
http://dx.doi.org/10.1038/s41698-023-00372-1
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