17 von Hoff, Katja Haberler, Christine Schmitt-Hoffner, Felix Schepke, Elizabeth de Rojas, Teresa Jacobs, Sandra Zapotocky, Michal Sumerauer, David Perek-Polnik, Marta Dufour, Christelle van Vuurden, Dannis Slavc, Irene Gojo, Johannes Pickles, Jessica C Gerber, Nicolas U Massimino, Maura Gil-da-Costa, Maria Joao Garami, Miklos Kumirova, Ella Sehested, Astrid Scheie, David Cruz, Ofelia Moreno, Lucas Cho, Jaeho Zeller, Bernward Bovenschen, Niels Grotzer, Michael Alderete, Daniel Snuderl, Matija Zheludkova, Olga Golanov, Andrey Okonechnikov, Konstantin Mynarek, Martin Juhnke, Björn Ole Rutkowski, Stefan Schüller, Ulrich Pizer, Barry von Zezschwitz, Barbara Kwiecien, Robert Wechsung, Maximilian Konietschke, Frank Hwang, Eugene I Sturm, Dominik Pfister, Stefan M von Deimling, Andreas Rushing, Elisabeth J Ryzhova, Marina Hauser, Peter Łastowska, Maria Wesseling, Pieter Giangaspero, Felice Hawkins, Cynthia Figarella-Branger, Dominique Eberhart, Charles Burger, Peter Gessi, Marco Korshunov, Andrey Jacques, Tom S Capper, David Pietsch, Torsten Kool, Marcel Brainbank Unit Bonn Neuro-Oncology Neuro-Oncology Oxford Univ. Press Oxford 1523-5866 10.1093/neuonc/noab136 English 1597 - 1611 9 23 Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as 'CNS-primitive neuroectodermal tumors' (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies.Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed.DNA methylation profiling of 'CNS-PNET' classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively.The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments. PUB:(DE-HGF)16, ; 0, ; Brain Neoplasms: diagnosis Brain Neoplasms: genetics Brain Neoplasms: therapy Central Nervous System Neoplasms: diagnosis Central Nervous System Neoplasms: genetics Central Nervous System Neoplasms: therapy Forkhead Transcription Factors Humans Neoplasms, Germ Cell and Embryonal: diagnosis Neoplasms, Germ Cell and Embryonal: genetics Neoplasms, Germ Cell and Embryonal: therapy Neuroectodermal Tumors, Primitive: diagnosis Neuroectodermal Tumors, Primitive: genetics Neuroectodermal Tumors, Primitive: therapy Pathology, Molecular Retrospective Studies CNS NB-FOXR2 CNS embryonal tumor CNS-PNET DNA methylation profiling ETMR FOXR2 protein, human Forkhead Transcription Factors Journal Article 2021 DZNE-2021-01455 2021 pmc:PMC8408859 pmid:34077956 https://pub.dzne.de/record/162800 https://doi.org/10.1093/neuonc/noab136