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Acta Neuropathol. 2016 Jun;131(6):847-63. doi: 10.1007/s00401-016-1549-x. Epub 2016 Feb 26.

Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors.

Author information

1
Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, QC, Canada.
2
Department of Human Genetics, McGill University, Montreal, QC, Canada.
3
McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
4
Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada.
5
Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada.
6
Department of Biochemistry and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada.
7
Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany.
8
Department of Neuropathology, Institute of Pathology, Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
9
Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany.
10
Department of Radiology, University Hospital Münster, Münster, Germany.
11
Division of Pediatric Neurology, University Children's Hospital, Münster, Germany.
12
Department of Pathology, CHU Sainte-Justine, Montreal, Canada.
13
Division of Neuropathology, UCL Institute of Neurology, London, UK.
14
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
15
Department of Pediatrics, The University of Melbourne, Melbourne, Australia.
16
Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.
17
Department of Neurology, The Royal Children's Hospital, Melbourne, Australia.
18
Murdoch Childrens Research Institute, Melbourne, Australia.
19
VUMC School of Medical Sciences, Amsterdam, The Netherlands.
20
Department of Anatomical Pathology, Royal Children's Hospital, Melbourne, Australia.
21
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
22
Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Heidelberg, Germany.
23
Department of Pathology, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
24
Departments of Oncology and Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada.
25
Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
26
Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
27
Department of Neurosurgery, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
28
Epilepsy Society, Chalfont St Peter, Buckinghamshire, UK.
29
Institute of Neuropathology, University Hospital Münster, Münster, Germany.
30
Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, McGill University, Montreal, QC, Canada.
31
Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada.
32
Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, QC, Canada. william.foulkes@mcgill.ca.
33
Department of Human Genetics, McGill University, Montreal, QC, Canada. william.foulkes@mcgill.ca.
34
Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada. william.foulkes@mcgill.ca.
35
Department of Medical Genetics and Cancer Research Program, Research Institute McGill University Health Centre, Montreal, QC, Canada. william.foulkes@mcgill.ca.

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.

KEYWORDS:

Brain development; Epilepsy; FGFR signaling; Molecular etiology; Targeted therapy; Whole-exome sequencing

PMID:
26920151
PMCID:
PMC5039033
DOI:
10.1007/s00401-016-1549-x
[Indexed for MEDLINE]
Free PMC Article

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