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Acta Neuropathologica

, Volume 136, Issue 2, pp 211–226 | Cite as

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

  • Kristian W. Pajtler
  • Ji Wen
  • Martin Sill
  • Tong Lin
  • Wilda Orisme
  • Bo Tang
  • Jens-Martin Hübner
  • Vijay Ramaswamy
  • Sujuan Jia
  • James D. Dalton
  • Kelly Haupfear
  • Hazel A. Rogers
  • Chandanamali Punchihewa
  • Ryan Lee
  • John Easton
  • Gang Wu
  • Timothy A. Ritzmann
  • Rebecca Chapman
  • Lukas Chavez
  • Fredrick A. Boop
  • Paul Klimo
  • Noah D. Sabin
  • Robert Ogg
  • Stephen C. Mack
  • Brian D. Freibaum
  • Hong Joo Kim
  • Hendrik Witt
  • David T. W. Jones
  • Baohan Vo
  • Amar Gajjar
  • Stan Pounds
  • Arzu Onar-Thomas
  • Martine F. Roussel
  • Jinghui Zhang
  • J. Paul Taylor
  • Thomas E. Merchant
  • Richard Grundy
  • Ruth G. Tatevossian
  • Michael D. Taylor
  • Stefan M. Pfister
  • Andrey Korshunov
  • Marcel Kool
  • David W. Ellison
Original Paper

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.

Keywords

Ependymoma Molecular heterogeneity DNA methylation profiling CXorf67 PRC2 H3 K27M H3 K27-trimethylation 

Notes

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’.

Compliance with ethical standards

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Supplementary material

401_2018_1877_MOESM1_ESM.pdf (5.2 mb)
Supplementary material 1 (PDF 5357 kb)

References

  1. 1.
    Alexander T, Nolte C, Krumlauf R (2009) Hox genes and segmentation of the hindbrain and axial skeleton. Annu Rev Cell Dev Biol 25:431–456.  https://doi.org/10.1146/annurev.cellbio.042308.113423 CrossRefPubMedGoogle Scholar
  2. 2.
    Bayliss J, Mukherjee P, Lu C, Jain SU, Chung C, Martinez D et al (2016) Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas. Sci Transl Med 8:366ra161.  https://doi.org/10.1126/scitranslmed.aah6904 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DT, Kool M et al (2013) Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24:660–672.  https://doi.org/10.1016/j.ccr.2013.10.006 CrossRefPubMedGoogle Scholar
  4. 4.
    Bouffet E, Tabori U, Huang A, Bartels U (2009) Ependymoma: lessons from the past, prospects for the future. Childs Nerv Syst 25:1383–1384.  https://doi.org/10.1007/s00381-009-0915-6 CrossRefPubMedGoogle Scholar
  5. 5.
    Boulay G, Awad ME, Riggi N, Archer TC, Iyer S, Boonseng WE et al (2017) OTX2 activity at distal regulatory elements shapes the chromatin landscape of group 3 medulloblastoma. Cancer Discov 7:288–301.  https://doi.org/10.1158/2159-8290.CD-16-0844 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474.  https://doi.org/10.1038/nature26000 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Carter M, Nicholson J, Ross F, Crolla J, Allibone R, Balaji V et al (2002) Genetic abnormalities detected in ependymomas by comparative genomic hybridisation. Br J Cancer 86:929–939CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Dewaele B, Przybyl J, Quattrone A, Finalet Ferreiro J, Vanspauwen V, Geerdens E et al (2014) Identification of a novel, recurrent MBTD1-CXorf67 fusion in low-grade endometrial stromal sarcoma. Int J Cancer 134:1112–1122.  https://doi.org/10.1002/ijc.28440 CrossRefPubMedGoogle Scholar
  9. 9.
    Di Giovannantonio LG, Di Salvio M, Omodei D, Prakash N, Wurst W, Pierani A et al (2014) Otx2 cell-autonomously determines dorsal mesencephalon versus cerebellum fate independently of isthmic organizing activity. Development 141:377–388.  https://doi.org/10.1242/dev.102954 CrossRefPubMedGoogle Scholar
  10. 10.
    Dosztanyi Z, Csizmok V, Tompa P, Simon I (2005) IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics 21:3433–3434.  https://doi.org/10.1093/bioinformatics/bti541 CrossRefPubMedGoogle Scholar
  11. 11.
    Dosztanyi Z, Meszaros B, Simon I (2009) ANCHOR: web server for predicting protein binding regions in disordered proteins. Bioinformatics 25:2745–2746.  https://doi.org/10.1093/bioinformatics/btp518 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Dyer S, Prebble E, Davison V, Davies P, Ramani P, Ellison D et al (2002) Genomic imbalances in pediatric intracranial ependymomas define clinically relevant groups. Am J Pathol 161:2133–2141CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6:l1.  https://doi.org/10.1126/scisignal.2004088 CrossRefGoogle Scholar
  14. 14.
    Gessi M, Capper D, Sahm F, Huang K, von Deimling A, Tippelt S et al (2016) Evidence of H3 K27M mutations in posterior fossa ependymomas. Acta Neuropathol 132:635–637.  https://doi.org/10.1007/s00401-016-1608-3 CrossRefPubMedGoogle Scholar
  15. 15.
    Gessi M, Gielen GH, Dreschmann V, Waha A, Pietsch T (2015) High frequency of H3F3A (K27 M) mutations characterizes pediatric and adult high-grade gliomas of the spinal cord. Acta Neuropathol 130:435–437.  https://doi.org/10.1007/s00401-015-1463-7 CrossRefPubMedGoogle Scholar
  16. 16.
    Godfraind C, Kaczmarska JM, Kocak M, Dalton J, Wright KD, Sanford RA et al (2012) Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas. Acta Neuropathol 124:247–257.  https://doi.org/10.1007/s00401-012-0981-9 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hirate Y, Okamoto H (2006) Canopy1, a novel regulator of FGF signaling around the midbrain–hindbrain boundary in zebrafish. Curr Biol 16:421–427.  https://doi.org/10.1016/j.cub.2006.01.055 CrossRefPubMedGoogle Scholar
  18. 18.
    Hoffman LM, Donson AM, Nakachi I, Griesinger AM, Birks DK, Amani V et al (2014) Molecular sub-group-specific immunophenotypic changes are associated with outcome in recurrent posterior fossa ependymoma. Acta Neuropathol 127:731–745.  https://doi.org/10.1007/s00401-013-1212-8 CrossRefPubMedGoogle Scholar
  19. 19.
    Huang YJ, Acton TB, Montelione GT (2014) DisMeta: a meta server for construct design and optimization. Methods Mol Biol 1091:3–16.  https://doi.org/10.1007/978-1-62703-691-7_1 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Huber W, Carey VJ, Gentleman R, Anders S, Carlson M, Carvalho BS et al (2015) Orchestrating high-throughput genomic analysis with bioconductor. Nat Methods 12:115–121.  https://doi.org/10.1038/nmeth.3252 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Johann PD, Erkek S, Zapatka M, Kerl K, Buchhalter I, Hovestadt V et al (2016) Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29:379–393.  https://doi.org/10.1016/j.ccell.2016.02.001 CrossRefPubMedGoogle Scholar
  22. 22.
    Joyon N, Tauziede-Espariat A, Alentorn A, Giry M, Castel D, Capelle L et al (2017) K27M mutation in H3F3A in ganglioglioma grade I with spontaneous malignant transformation extends the histopathological spectrum of the histone H3 oncogenic pathway. Neuropathol Appl Neurobiol 43:271–276.  https://doi.org/10.1111/nan.12329 CrossRefPubMedGoogle Scholar
  23. 23.
    Kilday JP, Mitra B, Domerg C, Ward J, Andreiuolo F, Osteso-Ibanez T et al (2012) Copy number gain of 1q25 predicts poor progression-free survival for pediatric intracranial ependymomas and enables patient risk stratification: a prospective European clinical trial cohort analysis on behalf of the Children’s Cancer Leukaemia Group (CCLG), Societe Francaise d’Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP). Clin Cancer Res 18:2001–2011.  https://doi.org/10.1158/1078-0432.CCR-11-2489 CrossRefPubMedGoogle Scholar
  24. 24.
    Korshunov A, Witt H, Hielscher T, Benner A, Remke M, Ryzhova M et al (2010) Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28:3182–3190.  https://doi.org/10.1200/JCO.2009.27.3359 CrossRefPubMedGoogle Scholar
  25. 25.
    Ma X, Wang J, Wang J, Ma CX, Gao X, Patriub V et al (2017) The JAZF1-SUZ12 fusion protein disrupts PRC2 complexes and impairs chromatin repression during human endometrial stromal tumorogenesis. Oncotarget 8:4062–4078.  https://doi.org/10.18632/oncotarget.13270 PubMedCrossRefGoogle Scholar
  26. 26.
    Mack SC, Pajtler KW, Chavez L, Okonechnikov K, Bertrand KC, Wang X et al (2018) Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature 553:101–105.  https://doi.org/10.1038/nature25169 CrossRefPubMedGoogle Scholar
  27. 27.
    Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stutz AM et al (2014) Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506:445–450.  https://doi.org/10.1038/nature13108 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    McGuire CS, Sainani KL, Fisher PG (2009) Incidence patterns for ependymoma: a surveillance, epidemiology, and end results study. J Neurosurg 110:725–729.  https://doi.org/10.3171/2008.9.JNS08117 CrossRefPubMedGoogle Scholar
  29. 29.
    Mendrzyk F, Korshunov A, Benner A, Toedt G, Pfister S, Radlwimmer B et al (2006) Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 12:2070–2079.  https://doi.org/10.1158/1078-0432.CCR-05-2363 CrossRefPubMedGoogle Scholar
  30. 30.
    Micci F, Panagopoulos I, Bjerkehagen B, Heim S (2006) Consistent rearrangement of chromosomal band 6p21 with generation of fusion genes JAZF1/PHF1 and EPC1/PHF1 in endometrial stromal sarcoma. Cancer Res 66:107–112.  https://doi.org/10.1158/0008-5472.CAN-05-2485 CrossRefPubMedGoogle Scholar
  31. 31.
    Pajtler KW, Mack SC, Ramaswamy V, Smith CA, Witt H, Smith A et al (2017) The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 133:5–12.  https://doi.org/10.1007/s00401-016-1643-0 CrossRefPubMedGoogle Scholar
  32. 32.
    Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F et al (2015) Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27:728–743.  https://doi.org/10.1016/j.ccell.2015.04.002 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Panwalkar P, Clark J, Ramaswamy V, Hawes D, Yang F, Dunham C et al (2017) Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. Acta Neuropathol 134:705–714.  https://doi.org/10.1007/s00401-017-1752-4 CrossRefPubMedGoogle Scholar
  34. 34.
    Parker M, Mohankumar KM, Punchihewa C, Weinlich R, Dalton JD, Li Y et al (2014) C11orf95-RELA fusions drive oncogenic NF-kappaB signalling in ependymoma. Nature 506:451–455.  https://doi.org/10.1038/nature13109 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Piunti A, Hashizume R, Morgan MA, Bartom ET, Horbinski CM, Marshall SA et al (2017) Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas. Nat Med 23:493–500.  https://doi.org/10.1038/nm.4296 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Puelles E, Acampora D, Lacroix E, Signore M, Annino A, Tuorto F et al (2003) Otx dose-dependent integrated control of antero-posterior and dorso-ventral patterning of midbrain. Nat Neurosci 6:453–460.  https://doi.org/10.1038/nn1037 CrossRefPubMedGoogle Scholar
  37. 37.
    Punchihewa C, Lee R, Lin T, Orisme W, Dalton J, Aronica E et al (2014) Pediatric posterior fossa ependymomas consist of two molecular subgroups defined by gene expression and methylation profiling. Neuro Oncol 16:011Google Scholar
  38. 38.
    Raybaud C (2016) MR assessment of pediatric hydrocephalus: a road map. Childs Nerv Syst 32:19–41.  https://doi.org/10.1007/s00381-015-2888-y CrossRefPubMedGoogle Scholar
  39. 39.
    Raybaud C, Ramaswamy V, Taylor MD, Laughlin S (2015) Posterior fossa tumors in children: developmental anatomy and diagnostic imaging. Childs Nerv Syst 31:1661–1676.  https://doi.org/10.1007/s00381-015-2834-z CrossRefPubMedGoogle Scholar
  40. 40.
    Rodriguez D, Cheung MC, Housri N, Quinones-Hinojosa A, Camphausen K, Koniaris LG (2009) Outcomes of malignant CNS ependymomas: an examination of 2408 cases through the surveillance, epidemiology, and end results (SEER) database (1973–2005). J Surg Res 156:340–351.  https://doi.org/10.1016/j.jss.2009.04.024 CrossRefPubMedGoogle Scholar
  41. 41.
    Ryall S, Guzman M, Elbabaa SK, Luu B, Mack SC, Zapotocky M et al (2017) H3 K27M mutations are extremely rare in posterior fossa group A ependymoma. Childs Nerv Syst 33:1047–1051.  https://doi.org/10.1007/s00381-017-3481-3 CrossRefPubMedGoogle Scholar
  42. 42.
    Sgaier SK, Lao Z, Villanueva MP, Berenshteyn F, Stephen D, Turnbull RK et al (2007) Genetic subdivision of the tectum and cerebellum into functionally related regions based on differential sensitivity to engrailed proteins. Development 134:2325–2335.  https://doi.org/10.1242/dev.000620 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Sturm D, Bender S, Jones DT, Lichter P, Grill J, Becher O et al (2014) Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer 14:92–107.  https://doi.org/10.1038/nrc3655 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Swanson WJ, Vacquier VD (2002) The rapid evolution of reproductive proteins. Nat Rev Genet 3:137–144.  https://doi.org/10.1038/nrg733 CrossRefPubMedGoogle Scholar
  45. 45.
    Tihan T, Zhou T, Holmes E, Burger PC, Ozuysal S, Rushing EJ (2008) The prognostic value of histological grading of posterior fossa ependymomas in children: a Children’s Oncology Group study and a review of prognostic factors. Mod Pathol 21:165–177.  https://doi.org/10.1038/modpathol.3800999 CrossRefPubMedGoogle Scholar
  46. 46.
    U-King-Im J, Taylor MD, Raybaud C (2010) Posterior fossa ependymomas: new radiological classification with surgical correlation. Childs Nerv Syst 26:1765–1772.  https://doi.org/10.1007/s00381-010-1251-6 CrossRefPubMedGoogle Scholar
  47. 47.
    Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A et al (2015) Proteomics. Tissue-based map of the human proteome. Science 347:394.  https://doi.org/10.1126/science.1260419 CrossRefGoogle Scholar
  48. 48.
    van der Maaten L, Hinton G (2008) Visualizing data using t-SNE. J Mach Learn Res 9:2579–2605Google Scholar
  49. 49.
    Vinchon M, Leblond P, Noudel R, Dhellemmes P (2005) Intracranial ependymomas in childhood: recurrence, reoperation, and outcome. Childs Nerv Syst 21:221–226CrossRefPubMedGoogle Scholar
  50. 50.
    Wani K, Armstrong TS, Vera-Bolanos E, Raghunathan A, Ellison DW, Gilbertson R et al (2012) A prognostic gene expression signature in infratentorial ependymoma. Acta Neuropathol 123:727–738.  https://doi.org/10.1007/s00401-012-0941-4 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Wilkerson MD, Hayes DN (2010) ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics 26:1572–1573.  https://doi.org/10.1093/bioinformatics/btq170 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R et al (2011) Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20:143–157.  https://doi.org/10.1016/j.ccr.2011.07.007 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y et al (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444–450.  https://doi.org/10.1038/ng.2938 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Xue B, Dunbrack RL, Williams RW, Dunker AK, Uversky VN (2010) PONDR-FIT: a meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta 1804:996–1010.  https://doi.org/10.1016/j.bbapap.2010.01.011 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B et al (2013) Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45:602–612.  https://doi.org/10.1038/ng.2611 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Kristian W. Pajtler
    • 1
    • 2
    • 3
  • Ji Wen
    • 4
  • Martin Sill
    • 1
    • 2
  • Tong Lin
    • 5
  • Wilda Orisme
    • 4
  • Bo Tang
    • 4
  • Jens-Martin Hübner
    • 1
    • 2
  • Vijay Ramaswamy
    • 6
    • 7
  • Sujuan Jia
    • 4
  • James D. Dalton
    • 4
  • Kelly Haupfear
    • 4
  • Hazel A. Rogers
    • 8
  • Chandanamali Punchihewa
    • 4
  • Ryan Lee
    • 4
  • John Easton
    • 9
  • Gang Wu
    • 9
  • Timothy A. Ritzmann
    • 8
  • Rebecca Chapman
    • 8
  • Lukas Chavez
    • 1
    • 2
  • Fredrick A. Boop
    • 10
  • Paul Klimo
    • 10
  • Noah D. Sabin
    • 11
  • Robert Ogg
    • 11
  • Stephen C. Mack
    • 7
    • 12
  • Brian D. Freibaum
    • 13
  • Hong Joo Kim
    • 13
  • Hendrik Witt
    • 1
    • 2
    • 3
  • David T. W. Jones
    • 1
    • 2
  • Baohan Vo
    • 14
  • Amar Gajjar
    • 15
  • Stan Pounds
    • 5
  • Arzu Onar-Thomas
    • 5
  • Martine F. Roussel
    • 14
  • Jinghui Zhang
    • 9
  • J. Paul Taylor
    • 13
    • 16
  • Thomas E. Merchant
    • 17
  • Richard Grundy
    • 8
  • Ruth G. Tatevossian
    • 4
  • Michael D. Taylor
    • 7
  • Stefan M. Pfister
    • 1
    • 2
    • 3
  • Andrey Korshunov
    • 18
    • 19
  • Marcel Kool
    • 1
    • 2
  • David W. Ellison
    • 9
  1. 1.Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)HeidelbergGermany
  2. 2.Division of Pediatric Neurooncology, German Cancer Consortium (DKTK)German Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Department of Pediatric Oncology, Hematology and ImmunologyUniversity HospitalHeidelbergGermany
  4. 4.Department of PathologySt. Jude Children’s Research HospitalMemphisUSA
  5. 5.Department of BiostatisticsSt. Jude Children’s Research HospitalMemphisUSA
  6. 6.Division of Hematology/OncologyHospital for Sick ChildrenTorontoCanada
  7. 7.Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research CentreThe Hospital for Sick ChildrenTorontoCanada
  8. 8.Children’s Brain Tumour Research Centre, University of NottinghamNottinghamUK
  9. 9.Department of Computational BiologySt. Jude Children’s Research HospitalMemphisUSA
  10. 10.Department of SurgerySt. Jude Children’s Research HospitalMemphisUSA
  11. 11.Department of Diagnostic ImagingSt. Jude Children’s Research HospitalMemphisUSA
  12. 12.Department of Pediatrics, Division of Pediatric Hematology and OncologyBaylor College of MedicineHoustonUSA
  13. 13.Department of Cell and Molecular BiologySt. Jude Children’s Research HospitalMemphisUSA
  14. 14.Department of Tumor Cell BiologySt. Jude Children’s Research HospitalMemphisUSA
  15. 15.Department of OncologySt. Jude Children’s Research HospitalMemphisUSA
  16. 16.Howard Hughes Medical InstituteChevy ChaseUSA
  17. 17.Department of Radiation OncologySt. Jude Children’s Research HospitalMemphisUSA
  18. 18.Department of NeuropathologyUniversity of HeidelbergHeidelbergGermany
  19. 19.Clinical Cooperation Unit NeuropathologyGerman Cancer Research Center (DKFZ)HeidelbergGermany

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