The molecular landscape of glioma in patients with Neurofibromatosis 1

Research output: Contribution to journalArticle

Authors

  • Fulvio D'Angelo
  • Michele Ceccarelli
  • Tala
  • Luciano Garofano
  • Jing Zhang
  • Véronique Frattini
  • Francesca P Caruso
  • Genevieve Lewis
  • Kristin D Alfaro
  • Luc Bauchet
  • Giulia Berzero
  • David Cachia
  • Mario Cangiano
  • Laurent Capelle
  • John de Groot
  • Francesco DiMeco
  • François Ducray
  • Walid Farah
  • Gaetano Finocchiaro
  • Stéphane Goutagny
  • Carlos Kamiya-Matsuoka
  • Cinzia Lavarino
  • Hugues Loiseau
  • Véronique Lorgis
  • Carlo E Marras
  • Ian McCutcheon
  • Do-Hyun Nam
  • Susanna Ronchi
  • Veronica Saletti
  • Romuald Seizeur
  • John Slopis
  • Mariona Suñol
  • Fanny Vandenbos
  • Pascale Varlet
  • Dominique Vidaud
  • Viviane Tabar
  • David E Reuss
  • Seung-Ki Kim
  • David Meyronet
  • Karima Mokhtari
  • Hector Salvador
  • Krishna P Bhat
  • Marica Eoli
  • Marc Sanson
  • Anna Lasorella
  • Antonio Iavarone

Colleges, School and Institutes

External organisations

  • BIOGEM Istituto di Ricerche Genetiche 'G. Salvatore', Ariano Irpino, Italy.
  • Department of Science and Technology, Università degli Studi del Sannio, Benevento, Italy.
  • Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
  • The University of Texas M.D. Anderson Cancer Center John Mendelsohn Faculty Center (FC7.3025) - Neuro-Oncology - Unit 0431, Houston, TX, USA.
  • Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center, Montpellier, France.
  • Sorbonne Universités UPMC Université Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, APHP, Paris, France.
  • Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
  • AP-HP, Hôpital de la Pitié-Salpêtrière, Service de Neurochirurgie, Paris, France.
  • Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • Hunterian Brain Tumor Research Laboratory CRB2 2M41, Baltimore, MD, USA.
  • Service de Neuro-Oncologie, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Department of Cancer Cell Plasticity, Cancer Research Center of Lyon, INSERM U1052, CNRS UMR5286, Lyon, France.
  • Department of Neurosurgery, CHU, Dijon, France.
  • Unit of Molecular Neuro-Oncology, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
  • Service de Neurochirurgie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.
  • Developmental Tumor Laboratory, Fundación Sant Joan de Déu, Barcelona, Spain.
  • Department of Neurosurgery, Bordeaux University Hospital. Labex TRAIL (ANR-10-LABX-57). EA 7435 - IMOTION Bordeaux University, Bordeaux, France.
  • Department of Medical Oncology, Centre GF Leclerc, Dijon, France.
  • Pediatric Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, Rome, Italy.
  • Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
  • Developmental Neurology Unit, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
  • Service de Neurochirurgie, Hôpital de la Cavale Blanche, CHRU de Brest, Université de Brest, Brest, France.
  • Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain.
  • Central Laboratory of Pathology, Pasteur I University Hospital, Nice, France.
  • IMA-Brain, Inserm U894, Institute of Psychiatry and Neuroscience of Paris, Paris, France.
  • EA7331, Université Paris Descartes, France; Service de Génétique et Biologie Moléculaires, Hôpital Cochin, AP-HP, Paris, France.
  • Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom.
  • Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Centre de Pathologie Et Neuropathologie Est Hospices Civils de Lyon, Lyon, France.
  • Pediatric Oncology Unit, Hospital Sant Joan de Déu, Esplugues, Barcelona, Spain.
  • Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA. al2179@cumc.columbia.edu.
  • Department of Neurology, Columbia University Medical Center, New York, NY, USA. ai2102@cumc.columbia.edu.

Abstract

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.

Details

Original languageEnglish
Pages (from-to)176-187
Number of pages12
JournalNature Medicine
Volume25
Issue number1
Publication statusPublished - 10 Dec 2018

Keywords

  • Adolescent, Adult, Antigens, Neoplasm/metabolism, Brain Neoplasms/complications, Child, Child, Preschool, Cohort Studies, DNA Methylation/genetics, Female, Germ-Line Mutation/genetics, Glioma/complications, Humans, Male, Middle Aged, Neurofibromatosis 1/complications, Neurofibromin 1/genetics, Reproducibility of Results, T-Lymphocytes/immunology, Transcriptome/genetics, X-linked Nuclear Protein/genetics, Young Adult