Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular s
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RESEARCH
Comprehensive analysis of diverse low‑grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette‑forming glioneuronal tumor Calixto‑Hope G. Lucas1, Rohit Gupta1, Pamela Doo2, Julieann C. Lee1, Cathryn R. Cadwell1, Biswarathan Ramani1, Jeffrey W. Hofmann1, Emily A. Sloan1, Bette K. Kleinschmidt‑DeMasters3, Han S. Lee4, Matthew D. Wood5, Marjorie Grafe5, Donald Born6, Hannes Vogel6, Shahriar Salamat7, Diane Puccetti8, David Scharnhorst9, David Samuel10, Tabitha Cooney11, Elaine Cham12, Lee‑way Jin13, Ziad Khatib14, Ossama Maher14, Gabriel Chamyan15, Carole Brathwaite15, Serguei Bannykh16, Sabine Mueller17,18,19, Cassie N. Kline17,18, Anu Banerjee17, Alyssa Reddy17,18, Jennie W. Taylor18,19, Jennifer L. Clarke18,19, Nancy Ann Oberheim Bush18,19, Nicholas Butowski19, Nalin Gupta20, Kurtis I. Auguste20, Peter P. Sun20, Jarod L. Roland20, Corey Raffel20, Manish K. Aghi20, Philip Theodosopoulos20, Edward Chang20, Shawn Hervey‑Jumper20, Joanna J. Phillips1,20, Melike Pekmezci1, Andrew W. Bollen1, Tarik Tihan1, Susan Chang19, Mitchel S. Berger20, Arie Perry1,20 and David A. Solomon1*
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 encod‑ ing 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
*Correspondence: [email protected] 1 Division of Neuropathology, Department of Pathology, University of California, San Francisco, 513 Parnassus Avenue, Health Sciences West 451, San Francisco, CA 94143, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access
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