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Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas

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Abstract

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.

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Acknowledgements

Support at St. Jude was provided by the American Lebanese Syrian Associated Charities and by NCI grants CA-96832 (to M.R.) and CA096832-13 (to D.W.E.). The work was supported by the CERN Research Fellowship (to K.W.P.), the ICGC PedBrain Tumour Project funded by the German Cancer Aid (109252) and the German Federal Ministry of Education and Research (to S.M.P.), the KIKA grant (#90) (to M.K.). Support at the University of Nottingham was provided by ‘Fighting Ependymoma’ and the ‘Connie and Albert Taylor Trust’.

Author information

Author notes

  1. Kristian W. Pajtler, Ji Wen, Martin Sill and Tong Lin are co-first authors.

  2. Marcel Kool and David W. Ellison are co-senior authors.

Authors and Affiliations

  1. Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany

    Kristian W. Pajtler, Martin Sill, Jens-Martin Hübner, Lukas Chavez, Hendrik Witt, David T. W. Jones, Stefan M. Pfister & Marcel Kool

  2. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany

    Kristian W. Pajtler, Martin Sill, Jens-Martin Hübner, Lukas Chavez, Hendrik Witt, David T. W. Jones, Stefan M. Pfister & Marcel Kool

  3. Department of Pediatric Oncology, Hematology and Immunology, University Hospital, 69120, Heidelberg, Germany

    Kristian W. Pajtler, Hendrik Witt & Stefan M. Pfister

  4. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Ji Wen, Wilda Orisme, Bo Tang, Sujuan Jia, James D. Dalton, Kelly Haupfear, Chandanamali Punchihewa, Ryan Lee & Ruth G. Tatevossian

  5. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Tong Lin, Stan Pounds & Arzu Onar-Thomas

  6. Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada

    Vijay Ramaswamy

  7. Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada

    Vijay Ramaswamy, Stephen C. Mack & Michael D. Taylor

  8. Children’s Brain Tumour Research Centre, University of Nottingham, Nottingham, UK

    Hazel A. Rogers, Timothy A. Ritzmann, Rebecca Chapman & Richard Grundy

  9. Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    John Easton, Gang Wu, Jinghui Zhang & David W. Ellison

  10. Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Fredrick A. Boop & Paul Klimo

  11. Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Noah D. Sabin & Robert Ogg

  12. Department of Pediatrics, Division of Pediatric Hematology and Oncology, Baylor College of Medicine, Houston, TX, USA

    Stephen C. Mack

  13. Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Brian D. Freibaum, Hong Joo Kim & J. Paul Taylor

  14. Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Baohan Vo & Martine F. Roussel

  15. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Amar Gajjar

  16. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    J. Paul Taylor

  17. Department of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Thomas E. Merchant

  18. Department of Neuropathology, University of Heidelberg, Heidelberg, Germany

    Andrey Korshunov

  19. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Andrey Korshunov

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  1. Kristian W. Pajtler
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  2. Ji Wen
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  7. Jens-Martin Hübner
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  8. Vijay Ramaswamy
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  10. James D. Dalton
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  13. Chandanamali Punchihewa
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  16. Gang Wu
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  18. Rebecca Chapman
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  19. Lukas Chavez
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  20. Fredrick A. Boop
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  22. Noah D. Sabin
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  23. Robert Ogg
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  24. Stephen C. Mack
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  28. David T. W. Jones
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  29. Baohan Vo
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  30. Amar Gajjar
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  31. Stan Pounds
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  32. Arzu Onar-Thomas
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  33. Martine F. Roussel
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  34. Jinghui Zhang
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  35. J. Paul Taylor
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  36. Thomas E. Merchant
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  37. Richard Grundy
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  38. Ruth G. Tatevossian
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  39. Michael D. Taylor
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  40. Stefan M. Pfister
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  41. Andrey Korshunov
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  42. Marcel Kool
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Pajtler, K.W., Wen, J., Sill, M. et al. Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol 136, 211–226 (2018). https://doi.org/10.1007/s00401-018-1877-0

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