Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile
Por:
Nussbaumer G, Benesch M, Grabovska Y, Mackay A, Castel D, Grill J, Alonso MM, Antonelli M, Bailey S, Baugh JN, Biassoni V, Blattner Johnson M, Broniscer A, Carai A, Colafati GS, Colditz N, Corbacioglu S, Crampsie S, Entz-Werle N, Eyrich M, Friker LL, Frühwald MC, Garrè ML, Gerber NU, Giangaspero F, Gil-da-Costa MJ, Graf N, Hargrave D, Hauser P, Herrlinger U, Hoffmann M, Hulleman E, Izquierdo E, Jacobs S, Karremann M, Kattamis A, Kebudi R, Kortmann RD, Kwiecien R, Massimino M, Mastronuzzi A, Miele E, Morana G, Noack CM, Pentikainen V, Perwein T, Pfister SM, Pietsch T, Roka K, Rossi S, Rutkowski S, Schiavello E, Seidel C, Šterba J, Sturm D, Sumerauer D, Tacke A, Temelso S, Valentini C, van Vuurden D, Varlet P, Veldhuijzen van Zanten SEM, Vinci M, von Bueren AO, Warmuth-Metz M, Wesseling P, Wiese M, Wolff JEA, Zamecnik J, Morales-La Madrid A, Bison B, Gielen GH, Jones DTW, Jones C and Kramm CM
Publicada:
1 sep 2024
Ahead of Print:
8 may 2024
Resumen:
Background. The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established.
Methods. We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization.
Results. Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n = 19), pedHGG_A/B (n = 6), and pedHGG_MYCN (n = 5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS.
Conclusions. Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).
Key Points
The presence of gliomatosis cerebri (GC) phenotype may be considered as an independent dismal prognostic factor in hemispheric pediatric-type diffuse gliomas.
The methylome-based subtypes pediatric-type diffuse high-grade glioma (pedHGG)_RTK2A/B and (provisional) pedHGG_A/B were significantly associated with GC.
EGFR and BCOR alterations and rearrangements of chromosome 6 were the most common genetic features in pediatric GC.
Filiaciones:
Nussbaumer G:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
Benesch M:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
Grabovska Y:
Division of Molecular Pathology, Institute of Cancer Research, London, UK
Mackay A:
Division of Molecular Pathology, Institute of Cancer Research, London, UK
Castel D:
Department of Pediatric and Adolescent Oncology, Gustave Roussy, 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
Grill J:
Department of Pediatric and Adolescent Oncology, Gustave Roussy, 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
Alonso MM:
Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain
Solid Tumor Program, Center for the Applied Medical Research, Pamplona, Navarra, Spain
Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain
Antonelli M:
Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Rome, Italy
Bailey S:
Department of Paediatric Oncology, Sir James Spence Institute of Child Health, Royal Victoria Infirmary Queen Victoria Road, Newcastle upon Tyne, UK
Baugh JN:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Biassoni V:
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
Blattner Johnson M:
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Broniscer A:
Division of Hematology-Oncology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
Carai A:
Neurosurgery Unit, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy
Colafati GS:
Oncological Neuroradiology and Advanced Diagnostics Unit, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy
Colditz N:
Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
Corbacioglu S:
Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Regensburg, Regensburg, Germany
Crampsie S:
Division of Molecular Pathology, Institute of Cancer Research, London, UK
Entz-Werle N:
Pediatric Onco-Hematology Department - Pediatrics III, University Hospital of Strasbourg, Strasbourg, France
UMR CNRS 7021 - Laboratory of Bioimagery and Pathologies Team tumor signaling and therapeutic targets, University of Strasbourg, Illkirch, France
Eyrich M:
Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
Friker LL:
Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
Frühwald MC:
Pediatric and Adolescent Medicine, Swabian Children's Cancer Center, University Medical Center Augsburg, Augsburg, Germany
Garrè ML:
Neuro-Oncology Unit, IRCSS Istituto Giannina Gaslini, Genoa, Italy
Gerber NU:
Department of Oncology and Children's Research Centre, University Children's Hospital, Zurich, Switzerland
Giangaspero F:
Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University, Rome, Italy
Gil-da-Costa MJ:
Pediatric Oncology Department, University Hospital São João, Porto, Portugal
Graf N:
Department of Pediatric Oncology and Hematology, Saarland University, Homburg, Germany
Hargrave D:
Pediatric Oncology, Great Ormond Street Hospital for Children, London, UK
Hauser P:
Second Department of Pediatrics, Semmelweis University, Budapest, Hungary
Herrlinger U:
Division of Clinical Neuro-Oncology, Department of Neurology, University Hospital Bonn, Bonn, Germany
Hoffmann M:
Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
Hulleman E:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Izquierdo E:
Division of Molecular Pathology, Institute of Cancer Research, London, UK
Jacobs S:
Department of Pediatric Hematology and Oncology, University Hospitals Leuven, Belgium and Pediatric Oncology, Department of Oncology, KU Leuven, Belgium
Karremann M:
Department of Pediatric and Adolescent Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Kattamis A:
Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece
Kebudi R:
Division of Pediatric Hematology-Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
Kortmann RD:
Department of Radiation Oncology, University of Leipzig, Leipzig, Germany
Kwiecien R:
Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany
Massimino M:
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
Mastronuzzi A:
Department of Onco-Hematology, Gene and Cell Therapy, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy
Miele E:
Department of Onco-Hematology, Gene and Cell Therapy, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy
Morana G:
Department of Neurosciences, University of Turin, Turin, Italy
Noack CM:
Center of Radiology, Department of Diagnostic and Interventional Radiology and Neuroradiology, Hospital of Fulda, Fulda, Germany
Pentikainen V:
Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, Helsinki University Hospital, Helsinki, Finland
Perwein T:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
Pfister SM:
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany
National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany
Pietsch T:
Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
Roka K:
Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece
Rossi S:
Pathology Unit, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy
Rutkowski S:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Schiavello E:
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
Seidel C:
Department of Radiation Oncology, University of Leipzig, Leipzig, Germany
Šterba J:
Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
Sturm D:
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany
Sumerauer D:
Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
Tacke A:
Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
Temelso S:
Division of Molecular Pathology, Institute of Cancer Research, London, UK
Valentini C:
Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
van Vuurden D:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Varlet P:
GHU-Paris Psychiatry and Neuroscience, Sainte-Anne Hospital, Department of Neuropathology, Paris, France
Veldhuijzen van Zanten SEM:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
Vinci M:
Department of Onco-Hematology, Gene and Cell Therapy, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy
von Bueren AO:
Department of Pediatrics, Obstetrics and Gynecology, Division of Pediatric Hematology and Oncology, University Hospital Geneva, Geneva, Switzerland
Warmuth-Metz M:
Institute of Diagnostic and Interventional Neuroradiology, University of Würzburg, Würzburg, Germany
Wesseling P:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Pathology, Amsterdam UMC, Amsterdam, The Netherlands
Wiese M:
Neurosurgery Unit, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy
Wolff JEA:
AbbVie Inc, Oncology Development, North Chicago, IL, USA
Zamecnik J:
Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
Morales-La Madrid A:
Pediatric Neuro-Oncology, Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, Barcelona, Spain
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, University Augsburg, Faculty of Medicine, Germany
Gielen GH:
Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
Jones DTW:
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Jones C:
Division of Molecular Pathology, Institute of Cancer Research, London, UK
Kramm CM:
Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
Green Submitted, Green Published, hybrid
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