Skip to main content

Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA


Papillary glioneuronal tumor (PGNT) is a WHO-defined brain tumor entity that poses a major diagnostic challenge. Recently, SLC44A1PRKCA fusions have been described in PGNT. We subjected 28 brain tumors from different institutions histologically diagnosed as PGNT to molecular and morphological analysis. Array-based methylation analysis revealed that 17/28 tumors exhibited methylation profiles typical for other tumor entities, mostly dysembryoplastic neuroepithelial tumor and hemispheric pilocytic astrocytoma. Conversely, 11/28 tumors exhibited a unique profile, thus constituting a distinct methylation class PGNT. By screening the extended Heidelberg cohort containing over 25,000 CNS tumors, we identified three additional tumors belonging to this methylation cluster but originally histologically diagnosed otherwise. RNA sequencing for the detection of SLC44A1PRKCA fusions could be performed on 19 of the tumors, 10 of them belonging to the methylation class PGNT. In two additional cases, SLC44A1PRKCA fusions were confirmed by FISH. We detected fusions involving PRKCA in all cases of this methylation class with material available for analyses: the canonical SLC44A1PRKCA fusion was observed in 11/12 tumors, while the remaining case exhibited a NOTCH1-PRKCA fusion. Neither of the fusions was found in the tumors belonging to other methylation classes. Our results point towards a high misclassification rate of the morphological diagnosis PGNT and clearly demonstrate the necessity of molecular analyses. PRKCA fusions are highly diagnostic for PGNT, and detection by RNA sequencing enables the identification of rare fusion partners. Methylation analysis recognizes a unique methylation class PGNT irrespective of the nature of the PRKCA fusion.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Ahmed AK, Dawood HY, Gerard J, Smith TR (2017) Surgical resection and cellular proliferation index predict prognosis for patients with papillary glioneuronal tumor: systematic review and pooled analysis. World Neurosurg 107:534–541.

    Article  PubMed  Google Scholar 

  2. 2.

    Andreiuolo F, Varlet P, Tauziede-Espariat A, Junger ST, Dorner E, Dreschmann V et al (2018) Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features. Brain Pathol.

    Article  PubMed  Google Scholar 

  3. 3.

    Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD et al (2014) Minfi: a flexible and comprehensive bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30:1363–1369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Blumcke I, Coras R, Wefers AK, Capper D, Aronica E, Becker A et al (2018) Challenges in the histopathological classification of ganglioglioma and DNT: microscopic agreement studies and a preliminary genotype-phenotype analysis. Neuropathol Appl Neurobiol.

    Article  PubMed  Google Scholar 

  5. 5.

    Bridge JA, Liu XQ, Sumegi J, Nelson M, Reyes C, Bruch LA et al (2013) Identification of a novel, recurrent SLC44A1-PRKCA fusion in papillary glioneuronal tumor. Brain Pathol 23:121–128.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Capper D, Stichel D, Sahm F, Jones DTW, Schrimpf D, Sill M et al (2018) Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience. Acta Neuropathol 136:181–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Gessi M, Abdel Moneim Y, Hammes J, Waha A, Pietsch T (2014) FGFR1 N546 K mutation in a case of papillary glioneuronal tumor (PGNT). Acta Neuropathol 127:935–936.

    Article  PubMed  Google Scholar 

  9. 9.

    Goode B, Mondal G, Hyun M, Ruiz DG, Lin YH, Van Ziffle J et al (2018) A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nat Commun 9:810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Komori T, Scheithauer BW, Anthony DC, Rosenblum MK, McLendon RE, Scott RM et al (1998) Papillary glioneuronal tumor: a new variant of mixed neuronal-glial neoplasm. Am J Surg Pathol 22:1171–1183

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Louis DN, International Agency for Research on Cancer., World Health Organization (2007) WHO classification of tumours of the central nervous system. International Agency for Research on Cancer, Lyon

    Google Scholar 

  12. 12.

    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Ellison DW, Figarella-Branger D, International Agency for Research on Cancer et al (2016) WHO classification of tumours of the central nervous system. International Agency For Research On Cancer, Lyon

    Google Scholar 

  14. 14.

    Martiny-Baron G, Fabbro D (2007) Classical PKC isoforms in cancer. Pharmacol Res 55:477–486.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    McPherson A, Hormozdiari F, Zayed A, Giuliany R, Ha G, Sun MG et al (2011) deFuse: an algorithm for gene fusion discovery in tumor RNA-Seq data. PLoS Comput Biol 7:e1001138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Nagaishi M, Nobusawa S, Matsumura N, Kono F, Ishiuchi S, Abe T et al (2016) SLC44A1-PRKCA fusion in papillary and rosette-forming glioneuronal tumors. J Clin Neurosci 23:73–75.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Pages M, Lacroix L, Tauziede-Espariat A, Castel D, Daudigeos-Dubus E, Ridola V et al (2015) Papillary glioneuronal tumors: histological and molecular characteristics and diagnostic value of SLC44A1-PRKCA fusion. Acta Neuropathol Commun 3:85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Reinhardt A, Stichel D, Schrimpf D, Sahm F, Korshunov A, Reuss DE et al (2018) Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wild-type glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol 136:273–291.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S et al (2017) DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol 18:682–694.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Sievers P, Stichel D, Schrimpf D, Sahm F, Koelsche C, Reuss DE et al (2018) FGFR1:tACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma. Acta Neuropathol 136:293–302.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437.

    Article  CAS  Google Scholar 

Download references


We thank V. Zeller, U. Vogel, H. Y. Nguyen, L. Dörner, U. Lass, A. Habel, K. Lindenberg, S. Kocher, and R. Quan for their extraordinary technical support, and the microarray unit of the DKFZ Genomics and Proteomics Core Facility for Illumina DNA methylation array analysis support. This study was partly supported by the Else Kröner-Fresenius Stiftung (2107_EKES.24) and the Molecular Neuropathology 2.0 study funded by the Deutsche Kinderkrebsstiftung. U.S. is supported by the Fördergemeinschaft Kinderkrebszentrum Hamburg. Part of the study was funded by the National Institute for Health Research to UCLH Biomedical Research Centre (BRC399/NS/RB/101410). Sebastian Brandner is also supported by the Department of Health’s NIHR Biomedical Research Centre’s funding scheme.

Author information



Corresponding author

Correspondence to Andreas von Deimling.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.


Supplementary Material 1 Unsupervised hierarchical clustering of the overall cohort of cases (n = 31) plus reference cases (n = 130). PGNT: histological defined papillary glioneuronal tumors; RGNT: MC rosette-forming glioneuronal tumor; DNT: MC dysembryoplastic neuroepithelial tumor; PA MID: MC midline pilocytic astrocytoma; PA PF: MC posterior fossa pilocytic astrocytoma; DLGNT: MC diffuse leptomeningeal glioneuronal tumor; CN: MC central neurocytoma; EP RELA: MC ependymoma RELA fused; PXA: MC pleomorphic xanthoastrocytoma; LGG MYB: MC low-grade glioma, MYB/MYBL1; PA HEMI: MC hemispheric pilocytic astrocytoma; NORM HEMI: MC normal hemispheric cortex; GG: MC ganglioglioma; CG: MC chordoid glioma of the third ventricle (TIFF 33,182 kb)


Supplementary Material 2 Clinical and molecular characteristics of the whole cohort (n = 31). *Identified tumors in large t-SNE plot belonging to MC PGNT, but originally histologically diagnosed otherwise (DOCX 20 kb)


Supplementary Material 3 Fisher’s exact test showing a significant association between MC PGNT and presence of fusions involving PRKCA (p < 0.0001). (TIFF 9000 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hou, Y., Pinheiro, J., Sahm, F. et al. Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA. Acta Neuropathol 137, 837–846 (2019).

Download citation


  • Papillary glioneuronal tumor
  • SLC44A1
  • NOTCH1
  • DNA methylation
  • RNA sequencing