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Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

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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.

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Acknowledgments

We particularly thank the family for their unfailing support of this work. We thank Nancy Hamel, Susanne Peetz-Dienhart, Yvonne Crede, Tamiko Nishimura, Christian Young, Leanne de Kock, Leora Witkowski, Greta Gillies, Simon Harvey, Wirginia Maixner, Reina Zühlke-Jenisch and Kate Pope for providing expert technical assistance. We would like to thank Pierre Lepage and Rosalie Fréchette from McGill University and Genome Quebec Innovation Centre for their help with Fluidigm experiments. BR is funded by Fundacion Alfonso Martin Escudero and the FQRNT-Merit scholarship program for foreign students (185460). TG is funded by a CIHR postdoctoral fellowship. PJL is supported by an NHMRC Australia Career Development Fellowship (APP1032364). AMB is the recipient of a Canada Research Chair in Structural Biology, NJ is the recipient of a FRQS Chaire de Recherche, JM is the recipient of a Canada Research Chair in Genomics. Tissues were partly provided from Epilepsy Society Brain and Tissue Bank (UCL, Institute of Neurology; London, United Kingdom supported though the Katy Baggott foundation). This work was partly undertaken at University College London and University College London Hospital, who receive part of their funding from the Department of Health Biomedical Centre scheme.

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Authors and Affiliations

  1. Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, QC, Canada

    Barbara Rivera & William D. Foulkes

  2. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Barbara Rivera, Tenzin Gayden, Jian Carrot-Zhang, Javad Nadaf, Damien Faury, Michele Zeinieh, Somayyeh Fahiminiya, Eric Bareke, Celia M. T. Greenwood, Nada Jabado, William D. Foulkes & Jacek Majewski

  3. McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada

    Jian Carrot-Zhang, Javad Nadaf, Somayyeh Fahiminiya, Eric Bareke & Jacek Majewski

  4. Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada

    Talia Boshari & William D. Foulkes

  5. Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada

    Romeo Blanc

  6. Department of Biochemistry and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada

    David L. Burk & Albert M. Berghuis

  7. Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany

    Ulrich Schüller

  8. Department of Neuropathology, Institute of Pathology, Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany

    Camelia M. Monoranu

  9. Pediatric Hematology and Oncology, University Children’s Hospital Münster, Münster, Germany

    Ronald Sträter & Kornelius Kerl

  10. Department of Radiology, University Hospital Münster, Münster, Germany

    Thomas Niederstadt

  11. Division of Pediatric Neurology, University Children’s Hospital, Münster, Germany

    Gerhard Kurlemann

  12. Department of Pathology, CHU Sainte-Justine, Montreal, Canada

    Benjamin Ellezam

  13. Division of Neuropathology, UCL Institute of Neurology, London, UK

    Zuzanna Michalak & Maria Thom

  14. Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK

    Zuzanna Michalak, Maria Thom & Sanjay M. Sisodiya

  15. Department of Pediatrics, The University of Melbourne, Melbourne, Australia

    Paul J. Lockhart & Richard J. Leventer

  16. Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia

    Paul J. Lockhart

  17. Department of Neurology, The Royal Children’s Hospital, Melbourne, Australia

    Richard J. Leventer

  18. Murdoch Childrens Research Institute, Melbourne, Australia

    Richard J. Leventer

  19. VUMC School of Medical Sciences, Amsterdam, The Netherlands

    Milou Ohm

  20. Department of Anatomical Pathology, Royal Children’s Hospital, Melbourne, Australia

    Duncan MacGregor

  21. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    David Jones

  22. Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Heidelberg, Germany

    David Jones

  23. Department of Pathology, Montreal Neurological Institute, McGill University, Montreal, QC, Canada

    Jason Karamchandani

  24. Departments of Oncology and Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada

    Celia M. T. Greenwood

  25. Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    Susanne Bens & Reiner Siebert

  26. Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland

    Magdalena Zakrzewska & Pawel P. Liberski

  27. Department of Neurosurgery, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland

    Krzysztof Zakrzewski

  28. Epilepsy Society, Chalfont St Peter, Buckinghamshire, UK

    Sanjay M. Sisodiya

  29. Institute of Neuropathology, University Hospital Münster, Münster, Germany

    Werner Paulus & Martin Hasselblatt

  30. Department of Pathology, Montreal Children’s Hospital, McGill University Health Centre, McGill University, Montreal, QC, Canada

    Steffen Albrecht

  31. Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada

    Nada Jabado

  32. Department of Medical Genetics and Cancer Research Program, Research Institute McGill University Health Centre, Montreal, QC, Canada

    William D. Foulkes

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  1. Barbara Rivera
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Corresponding author

Correspondence to William D. Foulkes.

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Conflict of interest

The authors declare no conflict of interest.

Ethical approval

The study was approved by the Institutional Review Board (IRB) of the Faculty of Medicine of McGill University. Participants were recruited in compliance with the second edition of the Canadian Tri-Council Policy Statement of Ethical Conduct for Research Involving Humans and Eligible Persons or Designates and signed a consent form in accordance with the IRB approvals.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Funding

This project was supported by the Fonds de Recherche du Quebec-Sante (NJ, JM, WDF); IZKF Münster (Ha3/019/15) and Deutsche Krebshilfe DKH110267 to MH; National Health and Medical Research Council of Australia, the Victorian Government’s Operational Infrastructure Support Program and Australian Government NHMRC IRIISS, the Murdoch Childrens Research Institute and the Campbell Edwards Trust to PL and RJL; IMF Münster and Deutsche Krebshilfe (111537) to KK; CIHR Grant MOP-114889 to AMB; a National Science Centre Grant No. 2014/15/B/NZ4/00744 to MZ; Infrastructure for the research on pediatric tumors is supported by KinderKrebsInitiative Buchholz/Holm-Seppensen to RS and SB; by the Wellcome Trust Grant 084730 to SMS.

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Rivera, B., Gayden, T., Carrot-Zhang, J. et al. Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. Acta Neuropathol 131, 847–863 (2016). https://doi.org/10.1007/s00401-016-1549-x

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  • DOI: https://doi.org/10.1007/s00401-016-1549-x

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