Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype
Abstract Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and cl...
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2024-11-01
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| author | Arnault Tauziède-Espariat Lea L. Friker Gunther Nussbaumer Brigitte Bison Volodia Dangouloff-Ros Alice Métais David Sumerauer Josef Zamecnik Martin Benesch Thomas Perwein Dannis van Vuurden Pieter Wesseling Andrés Morales La Madrid Maria Luisa Garrè Manila Antonelli Felice Giangaspero Torsten Pietsch Dominik Sturm David T. W. Jones Stefan M. Pfister Yura Grabovska Alan Mackay Chris Jones Jacques Grill Yassine Ajlil André O. von Bueren Michael Karremann Marion Hoffmann Christof M. Kramm Robert Kwiecien David Castel Gerrit H. Gielen Pascale Varlet |
| author_facet | Arnault Tauziède-Espariat Lea L. Friker Gunther Nussbaumer Brigitte Bison Volodia Dangouloff-Ros Alice Métais David Sumerauer Josef Zamecnik Martin Benesch Thomas Perwein Dannis van Vuurden Pieter Wesseling Andrés Morales La Madrid Maria Luisa Garrè Manila Antonelli Felice Giangaspero Torsten Pietsch Dominik Sturm David T. W. Jones Stefan M. Pfister Yura Grabovska Alan Mackay Chris Jones Jacques Grill Yassine Ajlil André O. von Bueren Michael Karremann Marion Hoffmann Christof M. Kramm Robert Kwiecien David Castel Gerrit H. Gielen Pascale Varlet |
| author_sort | Arnault Tauziède-Espariat |
| collection | DOAJ |
| description | Abstract Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4–17) with a median overall survival of 16.0 months (range 10.9–28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases. |
| format | Article |
| id | doaj-art-a314c4fae9f64dd98df77f621bcc505c |
| institution | Kabale University |
| issn | 2051-5960 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-a314c4fae9f64dd98df77f621bcc505c2024-11-24T12:47:17ZengBMCActa Neuropathologica Communications2051-59602024-11-0112111110.1186/s40478-024-01881-1Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotypeArnault Tauziède-Espariat0Lea L. Friker1Gunther Nussbaumer2Brigitte Bison3Volodia Dangouloff-Ros4Alice Métais5David Sumerauer6Josef Zamecnik7Martin Benesch8Thomas Perwein9Dannis van Vuurden10Pieter Wesseling11Andrés Morales La Madrid12Maria Luisa Garrè13Manila Antonelli14Felice Giangaspero15Torsten Pietsch16Dominik Sturm17David T. W. Jones18Stefan M. Pfister19Yura Grabovska20Alan Mackay21Chris Jones22Jacques Grill23Yassine Ajlil24André O. von Bueren25Michael Karremann26Marion Hoffmann27Christof M. Kramm28Robert Kwiecien29David Castel30Gerrit H. Gielen31Pascale Varlet32Department of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne HospitalInstitute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical CenterDivision of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of GrazDiagnostic and Interventional Neuroradiology, Faculty of Medicine, University of AugsburgPediatric Radiology Department, Hôpital Necker Enfants Malades, AP-HPDepartment of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne HospitalDepartment of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital MotolDepartment of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University in Prague and University Hospital MotolDivision of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of GrazDivision of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of GrazPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPediatric Neuro-Oncology, Pediatric Cancer Center Barcelona, Hospital Sant Joan de DeuNeuro-Oncology Unit, IRCSS Istituto Giannina GasliniDepartment of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza UniversityDepartment of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza UniversityInstitute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical CenterDivision of Pediatric Glioma Research, Hopp Children’s Cancer Center Heidelberg (KiTZ)Division of Pediatric Glioma Research, Hopp Children’s Cancer Center Heidelberg (KiTZ)Hopp Children’s Cancer Center Heidelberg (KiTZ)Division of Molecular Pathology, Institute of Cancer ResearchDivision of Molecular Pathology, Institute of Cancer ResearchDivision of Molecular Pathology, Institute of Cancer ResearchDepartment of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Université Paris-SaclayDepartment of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Université Paris-SaclayDepartment of Pediatrics, Obstetrics and Gynecology, Division of Pediatric Hematology and Oncology, University Hospital GenevaDepartment of Pediatric and Adolescent Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg UniversityDivision of Pediatric Hematology and Oncology, University Medical Center GöttingenDivision of Pediatric Hematology and Oncology, University Medical Center GöttingenInstitute of Biostatistics and Clinical Research, University of MünsterDepartment of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Université Paris-SaclayInstitute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical CenterDepartment of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne HospitalAbstract Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4–17) with a median overall survival of 16.0 months (range 10.9–28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases.https://doi.org/10.1186/s40478-024-01881-1Receptor tyrosine kinaseRTK2ARTK2BMethylationGliomatosis cerebriPediatric high-grade glioma |
| spellingShingle | Arnault Tauziède-Espariat Lea L. Friker Gunther Nussbaumer Brigitte Bison Volodia Dangouloff-Ros Alice Métais David Sumerauer Josef Zamecnik Martin Benesch Thomas Perwein Dannis van Vuurden Pieter Wesseling Andrés Morales La Madrid Maria Luisa Garrè Manila Antonelli Felice Giangaspero Torsten Pietsch Dominik Sturm David T. W. Jones Stefan M. Pfister Yura Grabovska Alan Mackay Chris Jones Jacques Grill Yassine Ajlil André O. von Bueren Michael Karremann Marion Hoffmann Christof M. Kramm Robert Kwiecien David Castel Gerrit H. Gielen Pascale Varlet Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype Acta Neuropathologica Communications Receptor tyrosine kinase RTK2A RTK2B Methylation Gliomatosis cerebri Pediatric high-grade glioma |
| title | Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype |
| title_full | Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype |
| title_fullStr | Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype |
| title_full_unstemmed | Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype |
| title_short | Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype |
| title_sort | diffuse pediatric high grade glioma of methylation based rtk2a and rtk2b subclasses present distinct radiological and histomolecular features including gliomatosis cerebri phenotype |
| topic | Receptor tyrosine kinase RTK2A RTK2B Methylation Gliomatosis cerebri Pediatric high-grade glioma |
| url | https://doi.org/10.1186/s40478-024-01881-1 |
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