The molecular landscape of glioma in patients with Neurofibromatosis 1

• Published in: Nature Medicine Vol. 25; no. 1; pp. 176 - 187
• Main Authors: D’Angelo, Fulvio, Ceccarelli, Michele, Tala, Garofano, Luciano, Zhang, Jing, Frattini, Véronique, Caruso, Francesca P., Lewis, Genevieve, Alfaro, Kristin D., Bauchet, Luc, Berzero, Giulia, Cachia, David, Cangiano, Mario, Capelle, Laurent, de Groot, John, DiMeco, Francesco, Ducray, François, Farah, Walid, Finocchiaro, Gaetano, Goutagny, Stéphane, Kamiya-Matsuoka, Carlos, Lavarino, Cinzia, Loiseau, Hugues, Lorgis, Véronique, Marras, Carlo E., McCutcheon, Ian, Nam, Do-Hyun, Ronchi, Susanna, Saletti, Veronica, Seizeur, Romuald, Slopis, John, Suñol, Mariona, Vandenbos, Fanny, Varlet, Pascale, Vidaud, Dominique, Watts, Colin, Tabar, Viviane, Reuss, David E., Kim, Seung-Ki, Meyronet, David, Mokhtari, Karima, Salvador, Hector, Bhat, Krishna P., Eoli, Marica, Sanson, Marc, Lasorella, Anna, Iavarone, Antonio
• Format: Journal Article Magazine Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2019; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/67; 631/67/1922; 631/67/69; Adolescent; Adult; Antigens, Neoplasm; Antigens, Neoplasm - metabolism; Biomedical and Life Sciences; Biomedicine; Brain Neoplasms; Brain Neoplasms - complications; Brain Neoplasms - genetics; Brain Neoplasms - immunology; Brain tumors; Cancer Research; Care and treatment; Child; Child, Preschool; Chromatin; Cohort Studies; Deoxyribonucleic acid; Development and progression; DNA; DNA Methylation; DNA Methylation - genetics; Female; Gene expression; Gene mutation; Gene regulation; Genetic aspects; Genetic disorders; Germ-Line Mutation; Germ-Line Mutation - genetics; Glioma; Glioma - complications; Glioma - genetics; Glioma - immunology; Gliomas; Health aspects; Homozygosity; Humans; Infectious Diseases; Isocitrate dehydrogenase; Life Sciences; Life span; Lymphocytes; Lymphocytes T; Male; MAP kinase; Metabolic Diseases; Middle Aged; Molecular Medicine; Mutation; Neoplasms; Neurofibromatosis; Neurofibromatosis 1; Neurofibromatosis 1 - complications; Neurofibromatosis 1 - genetics; Neurofibromin 1; Neurofibromin 1 - genetics; Neurological disorders; Neurosciences; p53 Protein; Patients; Physiological aspects; Recklinghausen's disease; Reproducibility of Results; Resource; Subgroups; T-Lymphocytes; T-Lymphocytes - immunology; Transcription; Transcriptome; Transcriptome - genetics; Tumors; X-linked Nuclear Protein; X-linked Nuclear Protein - genetics; Young Adult; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X; 1744-7933
• DOI: 10.1038/s41591-018-0263-8

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. An integrated analysis of glioma samples from patients with neurofibromatosis 1 annotates their mutational, epigenetic, transcriptional, and immunological features and uncovers similitudes with a subset of sporadic gliomas.