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OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type

Pediatric central nervous system (CNS) tumors differ substantially from their adult counterparts, are marked by considerable molecular and clinical heterogeneity, and diagnosis through histopathology alone can be challenging. Using DNA methylation-based CNS tumor classification in combination with c...

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Autores principales: Keck, Michaela-Kristina, Sill, Martin, Wittmann, Andrea, Kumar, Piyush Joshi, Stichel, Damian, Sievers, Philipp, Wefers, Annika K, Roncaroli, Federico, Hayden, James, McCabe, Martin G, Kranendonk, Mariëtte E G, Zapotocky, Michal, Vasiljevic, Alexandre, Schüller, Ulrich, Sturm, Dominik, Blattner-Johnson, Mirjam, von Deimling, Andreas, Korshunov, Andrey, Sahm, Felix, Perry, Arie, Solomon, David, Pfister, Stefan, Jones, David T W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164753/
http://dx.doi.org/10.1093/neuonc/noac079.579
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author Keck, Michaela-Kristina
Sill, Martin
Wittmann, Andrea
Kumar, Piyush Joshi
Stichel, Damian
Sievers, Philipp
Wefers, Annika K
Roncaroli, Federico
Hayden, James
McCabe, Martin G
Kranendonk, Mariëtte E G
Zapotocky, Michal
Vasiljevic, Alexandre
Schüller, Ulrich
Sturm, Dominik
Blattner-Johnson, Mirjam
von Deimling, Andreas
Korshunov, Andrey
Sahm, Felix
Perry, Arie
Solomon, David
Pfister, Stefan
Jones, David T W
author_facet Keck, Michaela-Kristina
Sill, Martin
Wittmann, Andrea
Kumar, Piyush Joshi
Stichel, Damian
Sievers, Philipp
Wefers, Annika K
Roncaroli, Federico
Hayden, James
McCabe, Martin G
Kranendonk, Mariëtte E G
Zapotocky, Michal
Vasiljevic, Alexandre
Schüller, Ulrich
Sturm, Dominik
Blattner-Johnson, Mirjam
von Deimling, Andreas
Korshunov, Andrey
Sahm, Felix
Perry, Arie
Solomon, David
Pfister, Stefan
Jones, David T W
author_sort Keck, Michaela-Kristina
collection PubMed
description Pediatric central nervous system (CNS) tumors differ substantially from their adult counterparts, are marked by considerable molecular and clinical heterogeneity, and diagnosis through histopathology alone can be challenging. Using DNA methylation-based CNS tumor classification in combination with copy number and RNAseq analysis, we identify a rare, novel pediatric CNS tumor type (n=32) which is characterized by focal high-level amplification and consecutive overexpression of one of the PLAG family genes – PLAGL1 or PLAGL2. It is epigenetically divergent from other known tumor types such as high-grade gliomas, medulloblastomas, embryonal tumors, or CNS sarcomas. The wide range of original histopathologic diagnosis rendered attests to their polyphenotypic nature in terms of morphology. We suggest that these tumors may arise from early to intermediate neural progenitor cells with some neuronal commitment. Using ChIPseq data, we show that both PLAGL1 and PLAGL2 act as transcription factors for: i) the oncogenic kinase RET, a potential drug target, that was overexpressed in our cohort; ii) components of the Wnt/β-Catenin pathway; iii) a set of imprinted genes, reported to regulate the imprinted gene network in mouse models, that was deregulated in the PLAGL-amplified tumors. Consequently, a 250-gene expression PLAGL-signature indicated dysregulation of imprinting control and differentiation/development as a prominent feature. We report differences regarding age and sex distribution between PLAGL1- and PLAGL2-amplified tumors and shed light on differences in clinical behavior and outcomes between these subtypes in male and female patients. PLAGL1-amplified tumors were more prevalent in school-age children and teenagers, while PLAGL2-amplified cases occurred in very young patients. Kaplan-Meier analysis showed a trend towards a more favorable outcome in patients with PLAGL1-amplified tumors and in female patients. Survival rates remained constant after 5 years with a five-/ten-year overall survival of 75% for PLAGL1, 24% for PLAGL2, 18% for male patients, and 88% for female patients.
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spelling pubmed-91647532022-06-05 OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type Keck, Michaela-Kristina Sill, Martin Wittmann, Andrea Kumar, Piyush Joshi Stichel, Damian Sievers, Philipp Wefers, Annika K Roncaroli, Federico Hayden, James McCabe, Martin G Kranendonk, Mariëtte E G Zapotocky, Michal Vasiljevic, Alexandre Schüller, Ulrich Sturm, Dominik Blattner-Johnson, Mirjam von Deimling, Andreas Korshunov, Andrey Sahm, Felix Perry, Arie Solomon, David Pfister, Stefan Jones, David T W Neuro Oncol Others (Not Fitting Any Other Category) Pediatric central nervous system (CNS) tumors differ substantially from their adult counterparts, are marked by considerable molecular and clinical heterogeneity, and diagnosis through histopathology alone can be challenging. Using DNA methylation-based CNS tumor classification in combination with copy number and RNAseq analysis, we identify a rare, novel pediatric CNS tumor type (n=32) which is characterized by focal high-level amplification and consecutive overexpression of one of the PLAG family genes – PLAGL1 or PLAGL2. It is epigenetically divergent from other known tumor types such as high-grade gliomas, medulloblastomas, embryonal tumors, or CNS sarcomas. The wide range of original histopathologic diagnosis rendered attests to their polyphenotypic nature in terms of morphology. We suggest that these tumors may arise from early to intermediate neural progenitor cells with some neuronal commitment. Using ChIPseq data, we show that both PLAGL1 and PLAGL2 act as transcription factors for: i) the oncogenic kinase RET, a potential drug target, that was overexpressed in our cohort; ii) components of the Wnt/β-Catenin pathway; iii) a set of imprinted genes, reported to regulate the imprinted gene network in mouse models, that was deregulated in the PLAGL-amplified tumors. Consequently, a 250-gene expression PLAGL-signature indicated dysregulation of imprinting control and differentiation/development as a prominent feature. We report differences regarding age and sex distribution between PLAGL1- and PLAGL2-amplified tumors and shed light on differences in clinical behavior and outcomes between these subtypes in male and female patients. PLAGL1-amplified tumors were more prevalent in school-age children and teenagers, while PLAGL2-amplified cases occurred in very young patients. Kaplan-Meier analysis showed a trend towards a more favorable outcome in patients with PLAGL1-amplified tumors and in female patients. Survival rates remained constant after 5 years with a five-/ten-year overall survival of 75% for PLAGL1, 24% for PLAGL2, 18% for male patients, and 88% for female patients. Oxford University Press 2022-06-03 /pmc/articles/PMC9164753/ http://dx.doi.org/10.1093/neuonc/noac079.579 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Others (Not Fitting Any Other Category)
Keck, Michaela-Kristina
Sill, Martin
Wittmann, Andrea
Kumar, Piyush Joshi
Stichel, Damian
Sievers, Philipp
Wefers, Annika K
Roncaroli, Federico
Hayden, James
McCabe, Martin G
Kranendonk, Mariëtte E G
Zapotocky, Michal
Vasiljevic, Alexandre
Schüller, Ulrich
Sturm, Dominik
Blattner-Johnson, Mirjam
von Deimling, Andreas
Korshunov, Andrey
Sahm, Felix
Perry, Arie
Solomon, David
Pfister, Stefan
Jones, David T W
OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type
title OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type
title_full OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type
title_fullStr OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type
title_full_unstemmed OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type
title_short OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type
title_sort othr-41. amplification of the plag family genes – plagl1 and plagl2 – is a key feature of a novel embryonal cns tumor type
topic Others (Not Fitting Any Other Category)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164753/
http://dx.doi.org/10.1093/neuonc/noac079.579
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