Papillary glioneuronal tumor (PGNT) is a WHO-defined brain tumor entity that poses a major diagnostic challenge. Recently, SLC44A1–PRKCA 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 SLC44A1–PRKCA fusions could be performed on 19 of the tumors, 10 of them belonging to the methylation class PGNT. In two additional cases, SLC44A1–PRKCA fusions were confirmed by FISH. We detected fusions involving PRKCA in all cases of this methylation class with material available for analyses: the canonical SLC44A1–PRKCA 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.
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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.
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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)
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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). https://doi.org/10.1007/s00401-019-01969-2
- Papillary glioneuronal tumor
- DNA methylation
- RNA sequencing