Philipp Sievers1,2, Martin Sill3,4, Daniel Schrimpf1,2, Damian Stichel1,2, David E Reuss1,2, Dominik Sturm3,5,6, Jürgen Hench7, Stephan Frank7, Lenka Krskova8,9, Ales Vicha8,10, Michal Zapotocky8,10, Brigitte Bison11, David Castel12,13, Jacques Grill12,13, Marie-Anne Debily12,14, Patrick N Harter15,16,17,18, Matija Snuderl19, Christof M Kramm20, Guido Reifenberger21,22, Andrey Korshunov1,2,3, Nada Jabado23,24,25, Pieter Wesseling26,27, Wolfgang Wick28,29, David A Solomon30,31, Arie Perry30,32, Thomas S Jacques33,34, Chris Jones35, Olaf Witt3,6,36, Stefan M Pfister3,4, Andreas von Deimling1,2, David T W Jones3,5, Felix Sahm1. 1. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 2. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 3. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. 4. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 5. Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. 6. Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology, University Hospital Heidelberg, Heidelberg, Germany. 7. Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland. 8. Prague Brain Tumor Research Group, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. 9. Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. 10. Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. 11. Institute of Diagnostic and Interventional Neuroradiology, University Hospital Würzburg, Würzburg, Germany. 12. Molecular Predictors and New Targets in Oncology, INSERM, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 13. Département de Cancérologie de l'Enfant et de l'Adolescent, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 14. Département de Biologie, Univ. Evry, Université Paris-Saclay, Evry, France. 15. Institute of Neurology (Edinger Institute), Goethe University, Frankfurt am Main, Germany. 16. German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany. 17. German Cancer Research Center (DKFZ), Heidelberg, Germany. 18. Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany. 19. Department of Pathology, NYU Langone Medical Center, New York, New York, USA. 20. Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany. 21. Institute of Neuropathology, Heinrich Heine University, Düsseldorf, Germany. 22. German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Germany. 23. Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada. 24. Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada. 25. The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada (N.J.). 26. Department of Pathology, Amsterdam University Medical Centers, Location VUmc and Brain Tumor Center Amsterdam, Amsterdam, the Netherlands (P.W.). 27. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands (P.W.). 28. Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 29. Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany. 30. Department of Pathology, University of California San Francisco (UCSF), San Francisco, California, USA (D.A.S., A.P.). 31. Clinical Cancer Genomics Laboratory, University of California San Francisco, San Francisco, California, USA (D.A.S.). 32. Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA (A.P.). 33. Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK. 34. Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. 35. Division of Molecular Pathology, Institute of Cancer Research, London, UK. 36. Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany (O.W.).
Abstract
BACKGROUND: Malignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern. METHODS: Here, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas. RESULTS: EGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations. CONCLUSIONS: Our findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.
BACKGROUND: Malignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern. METHODS: Here, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas. RESULTS: EGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations. CONCLUSIONS: Our findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.
Authors: Gerrit H Gielen; Joshua N Baugh; Dannis G van Vuurden; Sophie E M Veldhuijzen van Zanten; Darren Hargrave; Maura Massimino; Veronica Biassoni; Andres Morales la Madrid; Michael Karremann; Maria Wiese; Ulrich Thomale; Geert O Janssens; André O von Bueren; Thomas Perwein; Gunther Nussbaumer; Eelco W Hoving; Pitt Niehusmann; Marco Gessi; Robert Kwiecien; Simon Bailey; Torsten Pietsch; Felipe Andreiuolo; Christof M Kramm Journal: Neurooncol Adv Date: 2022-05-20
Authors: Chul Kee Park; Youn Soo Lee; Ho Shin Gwak; Hong In Yoon; Chan Woo Wee; Young Zoon Kim; Youngbeom Seo; Jung Ho Im; Yun Sik Dho; Kyung Hwan Kim; Je Beom Hong; Jae Sung Park; Seo Hee Choi; Min Sung Kim; Jangsup Moon; Kihwan Hwang; Ji Eun Park; Jin Mo Cho; Wan Soo Yoon; Se Hoon Kim; Young Il Kim; Ho Sung Kim; Kyoung Su Sung; Jin Ho Song; Min Ho Lee; Myung Hoon Han; Se Hoon Lee; Jong Hee Chang; Do Hoon Lim Journal: Brain Tumor Res Treat Date: 2021-04
Authors: David N Louis; Arie Perry; Pieter Wesseling; Daniel J Brat; Ian A Cree; Dominique Figarella-Branger; Cynthia Hawkins; H K Ng; Stefan M Pfister; Guido Reifenberger; Riccardo Soffietti; Andreas von Deimling; David W Ellison Journal: Neuro Oncol Date: 2021-08-02 Impact factor: 13.029