Christian Koelsche1, Mark Kriegsmann2, Felix K F Kommoss2, Damian Stichel3,4, Katharina Kriegsmann5, Christian Vokuhl6, Thomas G P Grünewald7,8,9,10, Laura Romero-Pérez7, Thomas Kirchner8,9,10, Enrique de Alava11, Juan Diaz-Martin11, Wolfgang Hartmann12, Daniel Baumhoer13, Cristina R Antonescu14, Karoly Szuhai15, Uta Flucke16, Uta Dirksen17, Stefan M Pfister18,19,20, David T W Jones18,21, Gunhild Mechtersheimer2, Andreas von Deimling22,23. 1. Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. christian.koelsche@med.uni-heidelberg.de. 2. Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. 3. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. 4. Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 5. Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany. 6. Department of Pediatric Pathology, University Hospital of Schleswig-Holstein, Kiel, Germany. 7. Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. 8. Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. 9. German Cancer Consortium (DKTK), partner site Munich, Munich, Germany. 10. German Cancer Research Center (DKFZ), Heidelberg, Germany. 11. Department of Pathology, Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital, CSIC/University of Sevilla/CIBERONC, 41013, Seville, Spain. 12. Division of Translational Pathology, Gerhard-Domagk-Institute for Pathology, University Hospital Münster, Westfalian Wilhelms University, Münster, Germany. 13. Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel and University of Basel, Basel, Switzerland. 14. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA. 15. Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. 16. Department of Pathology, Radboud University Hospital, Nijmegen, the Netherlands. 17. Cooperative Ewing Sarcoma Study group, University Hospital Essen, Essen, Germany. 18. Hopp Children's Cancer Center, NCT Heidelberg (KiTZ), Heidelberg, Germany. 19. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 20. Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany. 21. Pediatric Glioma Research Group, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 22. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. andreas.vondeimling@med.uni-heidelberg.de. 23. Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. andreas.vondeimling@med.uni-heidelberg.de.
Abstract
PURPOSE: Recent studies revealed divergent gene expression patterns in Ewing sarcoma (EwS) with canonical EWSR1-ETS gene fusions and undifferentiated round cell sarcomas (URCS) with EWSR1 rearrangements fused to the non-ETS gene NFATc2. Thus, the question arises whether the latter tumors really belong to EwS. METHODS: We collected five cases matching the group of URCS with EWSR1-NFATc2 fusion and performed DNA methylation and copy number profiling. Results were compared to methylation data of 30 EwS with various EWSR1-ETS fusions and one EwS with FUS-ERG fusion, 16 URCS with CIC rearrangement and 10 URCS with BCOR alteration and a total of 81 EWSR1-associated soft tissue sarcomas including 7 angiomatoid fibrous histiocytomas, 7 clear cell sarcomas of the soft tissue, 28 desmoplastic small round cell tumors, 10 extraskeletal myxoid chondrosarcomas and 29 myxoid liposarcomas. RESULTS: Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis of DNA methylation data revealed a homogeneous methylation cluster for URCS with EWSR1-NFATc2 fusion, which clearly segregated from EwS and the other subtypes. Copy number profiles of EWSR1-NFATc2 cases showed recurrent losses on chromosome 9q and segmental gains on 20q13 and 22q12 involving the EWSR1 and NFATc2 loci, respectively. CONCLUSION: In summary, URCS with EWSR1-NFATc2 fusion share a distinct DNA methylation signature and carry characteristic copy number alterations, which emphasizes that these sarcomas should be considered separately from EwS.
PURPOSE: Recent studies revealed divergent gene expression patterns in Ewing sarcoma (EwS) with canonical EWSR1-ETS gene fusions and undifferentiated round cell sarcomas (URCS) with EWSR1 rearrangements fused to the non-ETS gene NFATc2. Thus, the question arises whether the latter tumors really belong to EwS. METHODS: We collected five cases matching the group of URCS with EWSR1-NFATc2 fusion and performed DNA methylation and copy number profiling. Results were compared to methylation data of 30 EwS with various EWSR1-ETS fusions and one EwS with FUS-ERG fusion, 16 URCS with CIC rearrangement and 10 URCS with BCOR alteration and a total of 81 EWSR1-associated soft tissue sarcomas including 7 angiomatoid fibrous histiocytomas, 7 clear cell sarcomas of the soft tissue, 28 desmoplastic small round cell tumors, 10 extraskeletal myxoid chondrosarcomas and 29 myxoid liposarcomas. RESULTS: Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis of DNA methylation data revealed a homogeneous methylation cluster for URCS with EWSR1-NFATc2 fusion, which clearly segregated from EwS and the other subtypes. Copy number profiles of EWSR1-NFATc2 cases showed recurrent losses on chromosome 9q and segmental gains on 20q13 and 22q12 involving the EWSR1 and NFATc2 loci, respectively. CONCLUSION: In summary, URCS with EWSR1-NFATc2 fusion share a distinct DNA methylation signature and carry characteristic copy number alterations, which emphasizes that these sarcomas should be considered separately from EwS.
Entities:
Keywords:
DNA methylation; EWSR1; Ewing; Ewing like; NFATc2
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