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Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes
Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. He...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175344/ https://www.ncbi.nlm.nih.gov/pubmed/36973520 http://dx.doi.org/10.1007/s00401-023-02561-5 |
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author | Hoffmann, Lucas Coras, Roland Kobow, Katja López-Rivera, Javier A. Lal, Dennis Leu, Costin Najm, Imad Nürnberg, Peter Herms, Jochen Harter, Patrick N. Bien, Christian G. Kalbhenn, Thilo Müller, Markus Pieper, Tom Hartlieb, Till Kudernatsch, Manfred Hamer, Hajo Brandner, Sebastian Rössler, Karl Blümcke, Ingmar Jabari, Samir |
author_facet | Hoffmann, Lucas Coras, Roland Kobow, Katja López-Rivera, Javier A. Lal, Dennis Leu, Costin Najm, Imad Nürnberg, Peter Herms, Jochen Harter, Patrick N. Bien, Christian G. Kalbhenn, Thilo Müller, Markus Pieper, Tom Hartlieb, Till Kudernatsch, Manfred Hamer, Hajo Brandner, Sebastian Rössler, Karl Blümcke, Ingmar Jabari, Samir |
author_sort | Hoffmann, Lucas |
collection | PubMed |
description | Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-023-02561-5. |
format | Online Article Text |
id | pubmed-10175344 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-101753442023-05-13 Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes Hoffmann, Lucas Coras, Roland Kobow, Katja López-Rivera, Javier A. Lal, Dennis Leu, Costin Najm, Imad Nürnberg, Peter Herms, Jochen Harter, Patrick N. Bien, Christian G. Kalbhenn, Thilo Müller, Markus Pieper, Tom Hartlieb, Till Kudernatsch, Manfred Hamer, Hajo Brandner, Sebastian Rössler, Karl Blümcke, Ingmar Jabari, Samir Acta Neuropathol Original Paper Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-023-02561-5. Springer Berlin Heidelberg 2023-03-27 2023 /pmc/articles/PMC10175344/ /pubmed/36973520 http://dx.doi.org/10.1007/s00401-023-02561-5 Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Paper Hoffmann, Lucas Coras, Roland Kobow, Katja López-Rivera, Javier A. Lal, Dennis Leu, Costin Najm, Imad Nürnberg, Peter Herms, Jochen Harter, Patrick N. Bien, Christian G. Kalbhenn, Thilo Müller, Markus Pieper, Tom Hartlieb, Till Kudernatsch, Manfred Hamer, Hajo Brandner, Sebastian Rössler, Karl Blümcke, Ingmar Jabari, Samir Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes |
title | Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes |
title_full | Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes |
title_fullStr | Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes |
title_full_unstemmed | Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes |
title_short | Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes |
title_sort | ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in ptpn11/kras/nf1 and other ras-/map-kinase pathway genes |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175344/ https://www.ncbi.nlm.nih.gov/pubmed/36973520 http://dx.doi.org/10.1007/s00401-023-02561-5 |
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