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The  FGFR1  gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating  FGFR1  alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with  TACC1  as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different  FGFR1  events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with  FGFR1  alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with  FGFR1  alterations, and is uniquely characterized by  FGFR1  kinase domain hotspot missense mutations in combination with either  PIK3CA  or  PIK3R1  mutation, often with accompanying  NF1  or  PTPN11  mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by  FGFR1 - TACC1  fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying  NF1  or  PTPN11  mutation, but lacking the accompanying  PIK3CA  or  PIK3R1  mutation that characterizes RGNT. The glial component of LGNET with  FGFR1  alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with  FGFR1  alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with  BRAF  mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with  FGFR1  alterations.   Electronic supplementary material  The online version of this article (10.1186/s40478-020-01027-z) contains supplementary material, which is available to authorized users.

acta neuropathologica communications

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor