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

C.h Lucas ,Matthew D Wood,Han S Lee,Alyssa Reddy,Biswarathan Ramani,Diane Puccetti,Cathryn R Cadwell,Cassie Kline ,Arie Perry,J Hofmann ,Nalin Gupta,Shahriar Salamat,Tabitha Cooney,Joanna J Phillips,Melike Pekmezci,Serguei Bannykh,Susan M Chang ,Manish K Aghi,Corey Raffel,Bette K Kleinschmidt‐Demasters ,Nicholas Butowski,David Samuel,Elaine Cham,Mitchel S Berger,Hannes Vogel,Carole Brathwaite,Edward F Chang ,Gabriel Chamyan,Kurtis I Auguste,Andrew W Bollen,Pamela Doo,Peter Sun ,Jennie Taylor ,Philip V Theodosopoulos ,Marjorie R Grafe ,Ossama M Maher ,Anu Banerjee,Emily A Sloan,Julieann C Lee,David Scharnhorst,Jennifer Clarke ,Lee Way Jin ,Nancy Ann Oberheim Bush,Donald E Born ,Rohit Gupta,Ziad Khatib,Sabine Mueller,Jarod L Roland,Shawn Hervey-Jumper ,Tarık Tihan ,David A Solomon

doi:10.1186/s40478-020-01027-z

Abstract

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.

Highlights

Classification of glial and glioneuronal neoplasms is an evolving process that is no longer exclusively based on the combination of radiographic and histologic features, and includes both genetic and epigenetic signatures to facilitate the most accurate subtyping and prognostication [7, 13, 20, 29, 35]
Among the 21 low-grade neuroepithelial tumor (LGNET) with either FGFR1 p.N546 or p.K656 hotspot mutations, a second non-hotspot missense mutation in FGFR1 was identified in 8 tumors, which were uniformly present in cis as the hotspot mutation when phasing was possible (n = 4)
Through combining histologic, genomic, and epigenetic profiling on a series of 30 LGNET with FGFR1 alterations, we have identified that some tumor entities (RGNT and extraventricular neurocytoma (EVN)) have a distinct pattern of genetic alterations, while other tumor entities have overlapping/indistinct patterns precluding accurate classification based solely on genetic aberrations (Fig. 8)

Summary

Introduction

Classification of glial and glioneuronal neoplasms is an evolving process that is no longer exclusively based on the combination of radiographic and histologic features, and includes both genetic and epigenetic signatures to facilitate the most accurate subtyping and prognostication [7, 13, 20, 29, 35]. IDH1/2 mutation is present in both diffuse astrocytic neoplasms and oligodendroglial neoplasms in the cerebral hemispheres of young adults. BRAF mutations or fusions are present in a diverse spectrum of neuroepithelial tumors, including ganglioglioma, pilocytic astrocytoma, and pleomorphic xanthoastrocytoma (PXA). It is not possible to classify CNS tumors based solely on the presence of a single genetic aberration in most cases. The most accurate diagnostic classification incorporates assessment of any accompanying alterations, such as those commonly co-occurring with IDH1/2 mutation (e.g. TP53 and ATRX mutation in astrocytomas vs CIC, FUBP1, and TERT promoter mutations in oligodendrogliomas) or with BRAF mutation/fusion (e.g. CDKN2A homozygous deletion in PXA versus intact CDKN2A alleles in ganglioglioma and pilocytic astrocytoma) [6, 29, 30, 34, 44]

Methods

Results

Conclusion