Acta Neuropathologica Communications (Aug 2020)
Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor
- Calixto-Hope G. Lucas,
- Rohit Gupta,
- Pamela Doo,
- Julieann C. Lee,
- Cathryn R. Cadwell,
- Biswarathan Ramani,
- Jeffrey W. Hofmann,
- Emily A. Sloan,
- Bette K. Kleinschmidt-DeMasters,
- Han S. Lee,
- Matthew D. Wood,
- Marjorie Grafe,
- Donald Born,
- Hannes Vogel,
- Shahriar Salamat,
- Diane Puccetti,
- David Scharnhorst,
- David Samuel,
- Tabitha Cooney,
- Elaine Cham,
- Lee-way Jin,
- Ziad Khatib,
- Ossama Maher,
- Gabriel Chamyan,
- Carole Brathwaite,
- Serguei Bannykh,
- Sabine Mueller,
- Cassie N. Kline,
- Anu Banerjee,
- Alyssa Reddy,
- Jennie W. Taylor,
- Jennifer L. Clarke,
- Nancy Ann Oberheim Bush,
- Nicholas Butowski,
- Nalin Gupta,
- Kurtis I. Auguste,
- Peter P. Sun,
- Jarod L. Roland,
- Corey Raffel,
- Manish K. Aghi,
- Philip Theodosopoulos,
- Edward Chang,
- Shawn Hervey-Jumper,
- Joanna J. Phillips,
- Melike Pekmezci,
- Andrew W. Bollen,
- Tarik Tihan,
- Susan Chang,
- Mitchel S. Berger,
- Arie Perry,
- David A. Solomon
Affiliations
- Calixto-Hope G. Lucas
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- Rohit Gupta
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- Pamela Doo
- Institute for Human Genetics, University of California, San Francisco
- Julieann C. Lee
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- Cathryn R. Cadwell
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- Biswarathan Ramani
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- Jeffrey W. Hofmann
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- Emily A. Sloan
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- Bette K. Kleinschmidt-DeMasters
- Departments of Pathology, Neurology, and Neurosurgery, University of Colorado
- Han S. Lee
- Department of Pathology, Sutter Medical Center
- Matthew D. Wood
- Department of Pathology, Oregon Health & Science University
- Marjorie Grafe
- Department of Pathology, Oregon Health & Science University
- Donald Born
- Division of Neuropathology, Department of Pathology, Stanford University
- Hannes Vogel
- Division of Neuropathology, Department of Pathology, Stanford University
- Shahriar Salamat
- Department of Anatomic Pathology, University of Wisconsin-Madison
- Diane Puccetti
- Division of Hematology, Oncology, and Bone Marrow Transplant, Department of Pediatrics, University of Wisconsin-Madison
- David Scharnhorst
- Department of Pathology, Valley Children’s Hospital
- David Samuel
- Department of Hematology/Oncology, Valley Children’s Hospital
- Tabitha Cooney
- Department of Pediatric Oncology, Dana Farber Cancer Institute
- Elaine Cham
- Department of Pathology, UCSF Benioff Children’s Hospital Oakland
- Lee-way Jin
- Department of Pathology, University of California, Davis
- Ziad Khatib
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Nicklaus Children’s Hospital
- Ossama Maher
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Nicklaus Children’s Hospital
- Gabriel Chamyan
- Department of Pathology, Nicklaus Children’s Hospital
- Carole Brathwaite
- Department of Pathology, Nicklaus Children’s Hospital
- Serguei Bannykh
- Department of Pathology, Cedars-Sinai Medical Center
- Sabine Mueller
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California, San Francisco
- Cassie N. Kline
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California, San Francisco
- Anu Banerjee
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California, San Francisco
- Alyssa Reddy
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California, San Francisco
- Jennie W. Taylor
- Department of Neurology, University of California, San Francisco
- Jennifer L. Clarke
- Department of Neurology, University of California, San Francisco
- Nancy Ann Oberheim Bush
- Department of Neurology, University of California, San Francisco
- Nicholas Butowski
- Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco
- Nalin Gupta
- Department of Neurological Surgery, University of California, San Francisco
- Kurtis I. Auguste
- Department of Neurological Surgery, University of California, San Francisco
- Peter P. Sun
- Department of Neurological Surgery, University of California, San Francisco
- Jarod L. Roland
- Department of Neurological Surgery, University of California, San Francisco
- Corey Raffel
- Department of Neurological Surgery, University of California, San Francisco
- Manish K. Aghi
- Department of Neurological Surgery, University of California, San Francisco
- Philip Theodosopoulos
- Department of Neurological Surgery, University of California, San Francisco
- Edward Chang
- Department of Neurological Surgery, University of California, San Francisco
- Shawn Hervey-Jumper
- Department of Neurological Surgery, University of California, San Francisco
- Joanna J. Phillips
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- Melike Pekmezci
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- Andrew W. Bollen
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- Tarik Tihan
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- Susan Chang
- Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco
- Mitchel S. Berger
- Department of Neurological Surgery, University of California, San Francisco
- Arie Perry
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- David A. Solomon
- Division of Neuropathology, Department of Pathology, University of California, San Francisco
- DOI
- https://doi.org/10.1186/s40478-020-01027-z
- Journal volume & issue
-
Vol. 8,
no. 1
pp. 1 – 17
Abstract
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.
Keywords
- Rosette-forming glioneuronal tumor (RGNT)
- Extraventricular neurocytoma (EVN)
- Dysembryoplastic neuroepithelial tumor (DNT)
- Pilocytic astrocytoma
- FGFR1
- PIK3CA
