title: Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors.
abstract: Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.
authors.affiliation: Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, QC, Canada.|Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rivera
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Tenzin
authors.initials: T
authors.lastname: Gayden
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.|McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Carrot-Zhang
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.|McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
authors.forename: Javad
authors.initials: J
authors.lastname: Nadaf
authors.affiliation: Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Talia
authors.initials: T
authors.lastname: Boshari
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Damien
authors.initials: D
authors.lastname: Faury
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Michele
authors.initials: M
authors.lastname: Zeinieh
authors.affiliation: Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Romeo
authors.initials: R
authors.lastname: Blanc
authors.affiliation: Department of Biochemistry and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada.
authors.forename: David L
authors.initials: DL
authors.lastname: Burk
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.|McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.|McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Bareke
authors.affiliation: Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.affiliation: Department of Neuropathology, Institute of Pathology, Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: Camelia M
authors.initials: CM
authors.lastname: Monoranu
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Sträter
authors.affiliation: Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany.
authors.forename: Kornelius
authors.initials: K
authors.lastname: Kerl
authors.affiliation: Department of Radiology, University Hospital Münster, Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Niederstadt
authors.affiliation: Division of Pediatric Neurology, University Children's Hospital, Münster, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kurlemann
authors.affiliation: Department of Pathology, CHU Sainte-Justine, Montreal, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ellezam
authors.affiliation: Division of Neuropathology, UCL Institute of Neurology, London, UK.|Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Michalak
authors.affiliation: Division of Neuropathology, UCL Institute of Neurology, London, UK.|Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Thom
authors.affiliation: Department of Pediatrics, The University of Melbourne, Melbourne, Australia.|Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lockhart
authors.affiliation: Department of Pediatrics, The University of Melbourne, Melbourne, Australia.|Department of Neurology, The Royal Children's Hospital, Melbourne, Australia.|Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.affiliation: VUMC School of Medical Sciences, Amsterdam, The Netherlands.
authors.forename: Milou
authors.initials: M
authors.lastname: Ohm
authors.affiliation: Department of Anatomical Pathology, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Duncan
authors.initials: D
authors.lastname: MacGregor
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.affiliation: Department of Pathology, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Karamchandani
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.|Departments of Oncology and Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada.
authors.forename: Celia M T
authors.initials: CM
authors.lastname: Greenwood
authors.affiliation: Department of Biochemistry and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada.
authors.forename: Albert M
authors.initials: AM
authors.lastname: Berghuis
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Bens
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zakrzewska
authors.affiliation: Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
authors.forename: Pawel P
authors.initials: PP
authors.lastname: Liberski
authors.affiliation: Department of Neurosurgery, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Zakrzewski
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.|Epilepsy Society, Chalfont St Peter, Buckinghamshire, UK.
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Paulus
authors.affiliation: Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, McGill University, Montreal, QC, Canada.
authors.forename: Steffen
authors.initials: S
authors.lastname: Albrecht
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hasselblatt
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.|Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, QC, Canada. william.foulkes@mcgill.ca.|Department of Human Genetics, McGill University, Montreal, QC, Canada. william.foulkes@mcgill.ca.|Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada. william.foulkes@mcgill.ca.|Department of Medical Genetics and Cancer Research Program, Research Institute McGill University Health Centre, Montreal, QC, Canada. william.foulkes@mcgill.ca.
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.|McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
mesh_terms: D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005910:Glioma / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D055815:Young Adult
chemical_list: C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048493:Proto-Oncogene Proteins B-raf
keywords: Brain development; Epilepsy; FGFR signaling; Molecular etiology; Targeted therapy; Whole-exome sequencing