Michael Bockmayr1,2,3,4, Kim Harnisch5,6, Lara C Pohl1,2, Leonille Schweizer7,8, Theresa Mohme9, Meik Körner1,2, Malik Alawi10, Abigail K Suwala11,12,13, Mario M Dorostkar14,15, Camelia M Monoranu16, Martin Hasselblatt17, Annika K Wefers3,5, David Capper7,8, Jürgen Hench18, Stephan Frank18, Timothy E Richardson19, Ivy Tran20, Elisa Liu20, Matija Snuderl20, Lara Engertsberger21, Martin Benesch21, Andreas von Deimling11, Denise Obrecht1, Martin Mynarek1,3, Stefan Rutkowski1, Markus Glatzel5, Julia E Neumann5,22, Ulrich Schüller1,2,5. 1. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 2. Research Institute Children's Cancer Center Hamburg, Hamburg, Germany. 3. Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 4. Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany. 5. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 6. Institute for Neuropathology, University Hospital of Zurich, Zurich, Switzerland. 7. Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Berlin, Germany. 8. German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany. 9. Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 10. Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 11. Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. 12. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 13. Department of Neurological Surgery, UCSF, San Francisco, California, USA. 14. Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany. 15. German Center for Neurodegenerative Diseases, Munich, Germany. 16. Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany. 17. Institute of Neuropathology, University Hospital Münster, Münster, Germany. 18. Division of Neuropathology, Institute of Medical Genetics and Pathology, University of Basel, Basel, Switzerland. 19. Department of Pathology and Laboratory Medicine, Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, Texas, USA. 20. Department of Pathology, NYU Langone Health, New York City, New York, USA. 21. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria. 22. Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Abstract
BACKGROUND: Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients' clinical course are unknown. METHODS: We assembled a cohort of 185 tumors classified as MPE based on DNA methylation. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPE-B, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors. RESULTS: MPE-A occurred at a median age of 27 years and were enriched with tumors demonstrating papillary morphology and MGMT promoter hypermethylation. Half of these tumors could not be totally resected, and 85% relapsed within 10 years. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. MPE-B occurred at a median age of 45 years and included many tumors with a histological diagnosis of WHO grade II and tanycytic morphology. Patients within this subtype had a significantly better outcome with a relapse rate of 33% in 10 years (P = 3.4e-06). CONCLUSIONS: We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment.
BACKGROUND: Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients' clinical course are unknown. METHODS: We assembled a cohort of 185 tumors classified as MPE based on DNA methylation. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPE-B, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors. RESULTS: MPE-A occurred at a median age of 27 years and were enriched with tumors demonstrating papillary morphology and MGMT promoter hypermethylation. Half of these tumors could not be totally resected, and 85% relapsed within 10 years. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. MPE-B occurred at a median age of 45 years and included many tumors with a histological diagnosis of WHO grade II and tanycytic morphology. Patients within this subtype had a significantly better outcome with a relapse rate of 33% in 10 years (P = 3.4e-06). CONCLUSIONS: We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment.
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