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Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1

Abstract

Rosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this low-grade entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), initially identified through genome-wide DNA methylation screening among a cohort of > 30,000 tumors, of which most were diagnosed histologically as RGNT. FGFR1 hotspot mutations were observed in all tumors analyzed, with co-occurrence of PIK3CA mutations in about two-thirds of the cases (63%). Additional loss-of-function mutations in the tumor suppressor gene NF1 were detected in a subset of cases (33%). Notably, in contrast to most other low-grade gliomas, these tumors often displayed co-occurrence of two or even all three of these mutations. Our data highlight that molecularly defined RGNTs are characterized by highly recurrent combined genetic alterations affecting both MAPK and PI3K signaling pathways. Thus, these two pathways appear to synergistically interact in the formation of RGNT, and offer potential therapeutic targets for this disease.

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Acknowledgements

We thank H. Y. Nguyen, L. Dörner, V. Zeller, U. Lass, and J. Meyer for excellent technical support and the microarray unit of the DKFZ Genomics and Proteomics Core Facility for providing Illumina DNA methylation array-related services. We also thank the AP-HM Tumor Bank (authorization number: AC2018-31053; CRB BB-0033-00097) for providing tissue samples and the French National Cancer Institute (INCa) pathology network RENOCLIP-LOC (Clinical Pathology Neuro-Oncology Network for Rare Tumors of the Nervous System) for the histological review. D. Jones is supported by the Everest Centre for Low-grade Paediatric Brain Tumours (The Brain Tumour Charity, UK). F. Sahm is a fellow of the Else Kröner Excellence Program of the Else Kröner-Fresenius Stiftung (EKFS; 2017_EKES.24). S. Brandner is supported by the UK Department of Health’s NIHR Biomedical Research Centre’s funding scheme. This work was funded by the GCS GIRCI (Groupement Interrégional de Recherche Clinique et d’Innovation) Méditerranée (GlioMark project promoted by the AP-HM).

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Sievers, P., Appay, R., Schrimpf, D. et al. Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. Acta Neuropathol 138, 497–504 (2019). https://doi.org/10.1007/s00401-019-02038-4

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Keywords

  • Rosette-forming glioneuronal tumor
  • RGNT
  • Brain tumor
  • DNA methylation profile
  • Molecular classification
  • MAPK
  • PI3K
  • FGFR1
  • PIK3CA
  • NF1