Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: Results of an international, retrospective study

Katja Von Hoff, Christine Haberler, Felix Schmitt-Hoffner, Elizabeth Schepke, Teresa De Rojas, Sandra Jacobs, Michal Zapotocky, David Sumerauer, Marta Perek-Polnik, Christelle Dufour, Dannis Van Vuurden, Irene Slavc, Johannes Gojo, Jessica C. Pickles, Nicolas U. Gerber, Maura Massimino, Maria Joao Gil-Da-Costa, Miklos Garami, Ella Kumirova, Astrid SehestedDavid Scheie, Ofelia Cruz, Lucas Moreno, Jaeho Cho, Bernward Zeller, Niels Bovenschen, Michael Grotzer, Daniel Alderete, Matija Snuderl, Olga Zheludkova, Andrey Golanov, Konstantin Okonechnikov, Martin Mynarek, Björn Ole Juhnke, Stefan Rutkowski, Ulrich Schüller, Barry Pizer, Barbara Von Zezschwitz, Robert Kwiecien, Maximilian Wechsung, Frank Konietschke, Eugene I. Hwang, Dominik Sturm, Stefan M. Pfister, Andreas Von Deimling, Elisabeth J. Rushing, Marina Ryzhova, Peter Hauser, Maria Łastowska, Pieter Wesseling, Felice Giangaspero, Cynthia Hawkins, Dominique Figarella-Branger, Charles Eberhart, Peter Burger, Marco Gessi, Andrey Korshunov, Tom S. Jacques, David Capper, Torsten Pietsch, Marcel Kool

Research output: Contribution to journalArticlepeer-review


Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1597-1611
Number of pages15
Issue number9
StatePublished - Sep 1 2021


  • CNS embryonal tumor
  • DNA methylation profiling
  • ETMR

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research


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