Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype
Por:
Tauziède-Espariat A, Friker LL, Nussbaumer G, Bison B, Dangouloff-Ros V, Métais A, Sumerauer D, Zamecnik J, Benesch M, Perwein T, van Vuurden D, Wesseling P, Morales-La Madrid A, Garrè ML, Antonelli M, Giangaspero F, Pietsch T, Sturm D, Jones DTW, Pfister SM, Grabovska Y, Mackay A, Jones C, Grill J, Ajlil Y, von Bueren AO, Karremann M, Hoffmann M, Kramm CM, Kwiecien R, Castel D, Gielen GH and Varlet P
Publicada:
18 nov 2024
Ahead of Print:
18 nov 2024
Resumen:
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.
Filiaciones:
Tauziède-Espariat A:
Department of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne Hospital, 1, Rue Cabanis, 75014, Paris, France
Inserm, UMR 1266, IMA-Brain, Institut de Psychiatrie et Neurosciences de Paris, Paris, France
Friker LL:
Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
Nussbaumer G:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
Bison B:
Diagnostic and Interventional Neuroradiology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
Neuroradiological Reference Center for the Pediatric Brain Tumor (HIT) Studies of the German Society of Pediatric Oncology and Hematology, Faculty of Medicine, University Augsburg, Augsburg, Germany
Dangouloff-Ros V:
Pediatric Radiology Department, Hôpital Necker Enfants Malades, AP-HP, Paris, France
Université Paris Cité, UMR 1163, Institut Imagine and INSERM U1299, Paris, France
Métais A:
Department of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne Hospital, 1, Rue Cabanis, 75014, Paris, France
Inserm, UMR 1266, IMA-Brain, Institut de Psychiatrie et Neurosciences de Paris, Paris, France
Sumerauer D:
Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
Zamecnik J:
Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
Benesch M:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
Perwein T:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
van Vuurden D:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Wesseling P:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Pathology, Amsterdam UMC, Amsterdam, The Netherlands
Morales-La Madrid A:
Pediatric Neuro-Oncology, Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, Barcelona, Spain
Garrè ML:
Neuro-Oncology Unit, IRCSS Istituto Giannina Gaslini, Genoa, Italy
Antonelli M:
Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Rome, Italy
Giangaspero F:
Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Rome, Italy
Pietsch T:
Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
Sturm D:
Division of Pediatric Glioma Research, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
Jones DTW:
Division of Pediatric Glioma Research, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany
German Cancer Research Center (DKFZ), Heidelberg, Germany
Pfister SM:
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
National Center for Tumor Diseases (NCT), Heidelberg, Germany
Grabovska Y:
Division of Molecular Pathology, Institute of Cancer Research, London, UK
Mackay A:
Division of Molecular Pathology, Institute of Cancer Research, London, UK
Jones C:
Division of Molecular Pathology, Institute of Cancer Research, London, UK
Grill J:
Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France
U981, Molecular Predictors and New Targets in Oncology, Team Genomics and Oncogenesis of Pediatric Brain Tumors, INSERM, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Ajlil Y:
Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France
U981, Molecular Predictors and New Targets in Oncology, Team Genomics and Oncogenesis of Pediatric Brain Tumors, INSERM, Gustave Roussy, Université Paris-Saclay, Villejuif, France
von Bueren AO:
Department of Pediatrics, Obstetrics and Gynecology, Division of Pediatric Hematology and Oncology, University Hospital Geneva, Geneva, Switzerland
Cancer Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland
Karremann M:
Department of Pediatric and Adolescent Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
Hoffmann M:
Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
Kramm CM:
Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
Kwiecien R:
Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany
Castel D:
Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France
U981, Molecular Predictors and New Targets in Oncology, Team Genomics and Oncogenesis of Pediatric Brain Tumors, INSERM, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Gielen GH:
Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
Varlet P:
Department of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne Hospital, 1, Rue Cabanis, 75014, Paris, France
Inserm, UMR 1266, IMA-Brain, Institut de Psychiatrie et Neurosciences de Paris, Paris, France
Green Submitted, Green Published, gold
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