title: Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology.
abstract: Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and 'adult-type' diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82 % of DNETs and 40 % of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87 %), and MYB fusion genes were the most common genetic alteration in DAs (41 %). A BRAF:p.V600E mutation was present in 35 % of gangliogliomas and 18 % of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78 % of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Qaddoumi
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Wilda
authors.initials: W
authors.lastname: Orisme
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Santiago
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Kirti
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Dalton
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Haupfear
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Chandanamali
authors.initials: C
authors.lastname: Punchihewa
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: John
authors.initials: J
authors.lastname: Easton
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Mulder
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Boggs
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rusch
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Becksfort
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Shuoguo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Lee
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brat
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: V
authors.initials: V
authors.lastname: Peter Collins
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, USA.
authors.forename: Sonika
authors.initials: S
authors.lastname: Dahiya
authors.affiliation: Department of Pathology, Foothills Medical Center, Las Cruces, USA.
authors.forename: David
authors.initials: D
authors.lastname: George
authors.affiliation: Department of Pathology, Innovative Pathology Services Knoxville, Knoxville, USA.
authors.forename: William
authors.initials: W
authors.lastname: Konomos
authors.affiliation: Department of Pathology, Frenchay Hospital, Bristol, UK.
authors.forename: Kathreena M
authors.initials: KM
authors.lastname: Kurian
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: McFadden
authors.affiliation: Department of Pathology, University of São Paulo, Ribeirão Preto School of Medicine, São Paulo, Brazil.
authors.forename: Luciano Neder
authors.initials: LN
authors.lastname: Serafini
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Nickols
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, USA.
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Shurtleff
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Fredrick A
authors.initials: FA
authors.lastname: Boop
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Klimo
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, USA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Baker
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA.
authors.forename: Ruth G
authors.initials: RG
authors.lastname: Tatevossian
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA. david.ellison@stjude.org.
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
mesh_terms: D000293:Adolescent; D000328:Adult; D001254:Astrocytoma / Q000235:genetics / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins; D005260:Female; D018303:Ganglioglioma / Q000235:genetics / Q000473:pathology; D020570:Genes, myb; D020022:Genetic Predisposition to Disease; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016601:RNA-Binding Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C491719:MYBBP1A protein, human; C088831:MYBL1 protein, human; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; FGFR1; Glioma; Glioneuronal; MYB; RNA-seq
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