M Y Deng1,2, M Sill1,3, D Sturm1,2,4, D Stichel5,6, H Witt1,3,4, J Ecker1,4,7, A Wittmann1,2, J Schittenhelm8, M Ebinger9, M U Schuhmann10, D Figarella-Branger11, E Aronica12, O Staszewski13, M Preusser14, C Haberler15, M Lauten16, U Schüller17, C Hartmann18, M Snuderl19, C Dunham20, N Jabado21,22, P Wesseling23,24, M Deckert25, K Keyvani26, N Gottardo27,28,29, F Giangaspero30,31, K von Hoff32, D W Ellison33, T Pietsch34, C Herold-Mende35, T Milde1,4,7, O Witt1,4,7, M Kool1,3, A Korshunov5,6, W Wick36,37, A von Deimling5,6, S M Pfister1,3,4, D T W Jones1,2, F Sahm1,5,6. 1. Hopp Children's Cancer Center Heidelberg (KiTZ), University Hospital Heidelberg, Heidelberg, Germany. 2. Junior Research Group Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. 3. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany. 4. Department of Pediatric Oncology, Hematology and Immunology, Hopp Children's Cancer Center (KiTZ), University Hospital Heidelberg, Heidelberg, Germany. 5. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 6. Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 7. Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany. 8. Department of Neuropathology, Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital of Tübingen, Tübingen, Germany. 9. Department of Pediatric Hematology/Oncology, Children's University Hospital, Tübingen, Germany. 10. Department of Neurosurgery, Division of Pediatric Neurosurgery, University Hospital Tübingen, Tübingen, Germany. 11. Inst Neurophysiopathol, CHU Timone, Service d'Anatomie Pathologique et de Neuropathologie, Aix Marseille Univ, APHM, CNRS, INP, Marseille, France. 12. Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. 13. Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany. 14. Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria. 15. Institute of Neurology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria. 16. Department of Paediatrics, Paediatric Haematology and Oncology, University of Lübeck, Lübeck, Germany. 17. Department of Paediatric Haematology and Oncology and Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf, Research Institute at the Children's Cancer Centre Hamburg, Hamburg, Germany. 18. Department of Neuropathology, Institute of Pathology, Hannover Medical School (MHH), Hannover, Germany. 19. Department of Pathology, Division of Neuropathology, NYUSoM, New York, NY, USA. 20. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. 21. Department of Human Genetics, McGill University, Montreal, QC, Canada. 22. Department of Pediatrics, McGill University, McGill University Heath Centre Research Institute, Montreal, QC, Canada. 23. Department of Pathology, Amsterdam Universities Medical Centers/VUmc, Brain Tumor Center Amsterdam University Medical Center, Amsterdam, The. 24. Princess Máxima Center for Pediatric Oncology, Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands. 25. Institute of Neuropathology, University Hospital of Cologne, Cologne, Germany. 26. Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany. 27. Telethon Kids Institute, Perth, WA, Australia. 28. Centre for Child Health Research, University of Western Australia, Perth, WA, Australia. 29. Department of Oncology, Princess Margaret Hospital, Perth, WA, Australia. 30. Department of Radiological, Oncological and Anatomo-Pathological Science, Sapienza University of Rome, Rome, Italy. 31. IRCCS Neuromed, Pozzilli (Is), Italy. 32. Department of Paediatric Haematology and Oncology, Charité-Universitätsmedizin, Berlin, Germany. 33. Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA. 34. Institute of Neuropathology, Brain Tumor Reference Center of the Society for Neuropathology and Neuroanatomy, University of Bonn Medical Center, Bonn, Germany. 35. Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany. 36. Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany. 37. Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
Abstract
AIMS: DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. PATIENTS AND METHODS: DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. RESULTS: Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. CONCLUSIONS: DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.
AIMS: DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. PATIENTS AND METHODS: DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. RESULTS: Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. CONCLUSIONS: DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.
Authors: M Benesch; T Perwein; G Apfaltrer; T Langer; A Neumann; I B Brecht; M U Schuhmann; H Cario; M C Frühwald; K Vollert; M van Buiren; M Y Deng; A Seitz; C Haberler; M Mynarek; C Kramm; F Sahm; P A Robe; J W Dankbaar; K V Hoff; M Warmuth-Metz; B Bison Journal: AJNR Am J Neuroradiol Date: 2022-09-22 Impact factor: 4.966
Authors: Jessica C Pickles; Kshitij Mankad; Miren Aizpurua; Simon Ml Paine; Leslie R Bridges; Fernando Carceller; Elwira Szychot; Mark Walker; Amy R Fairchild; Talisa Mistry; Olumide Ogunbiyi; Alice Rolland; Thomas J Stone; Carryl Dryden; Dilys Addy; Elisa Garimberti; Jane Chalker; Felix Sahm; David Tw Jones; Darren Hargrave; Thomas S Jacques Journal: Neuropathol Appl Neurobiol Date: 2021-01-12 Impact factor: 8.090
Authors: David Capper; M Beatriz Lopes; Simone Schmid; David A Solomon; Eilis Perez; Anne Thieme; Bette K Kleinschmidt-DeMasters; Caterina Giannini; Annekathrin Reinhardt; Sylvia L Asa; Ozgur Mete; Damian Stichel; Christin Siewert; Carsten Dittmayer; Martin Hasselblatt; Werner Paulus; Christoph Nagel; Patrick N Harter; Jens Schittenhelm; Jürgen Honegger; Elisabeth Rushing; Roland Coras; Stefan M Pfister; Rolf Buslei; Arend Koch; Arie Perry; David T W Jones; Andreas von Deimling Journal: Acta Neuropathol Date: 2021-10-18 Impact factor: 17.088