The molecular landscape of glioma in patients with Neurofibromatosis 1

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 & 27 others 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, Colin Watts, 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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)176-187
Number of pages12
JournalNature Medicine
Volume25
Issue number1
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

Fingerprint

Neurofibromatosis 1
Glioma
Tumors
Genes
Isocitrate Dehydrogenase
T-cells
Neoplasms
Transcription
Phosphatidylinositol 3-Kinases
Chromatin
Mutation
Phosphotransferases
Neurofibromatosis 1 Genes
Telomere Homeostasis
Genetic Transcription
Antigens
Germ-Line Mutation
DNA Methylation
Epigenomics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

D’Angelo, F., Ceccarelli, M., Tala, Garofano, L., Zhang, J., Frattini, V., ... Iavarone, A. (2019). The molecular landscape of glioma in patients with Neurofibromatosis 1. Nature Medicine, 25(1), 176-187. https://doi.org/10.1038/s41591-018-0263-8

The molecular landscape of glioma in patients with Neurofibromatosis 1. / 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.

In: Nature Medicine, Vol. 25, No. 1, 01.01.2019, p. 176-187.

Research output: Contribution to journalArticle

D’Angelo, F, Ceccarelli, M, Tala, Garofano, L, Zhang, J, Frattini, V, Caruso, FP, Lewis, G, Alfaro, KD, Bauchet, L, Berzero, G, Cachia, D, Cangiano, M, Capelle, L, de Groot, J, DiMeco, F, Ducray, F, Farah, W, Finocchiaro, G, Goutagny, S, Kamiya-Matsuoka, C, Lavarino, C, Loiseau, H, Lorgis, V, Marras, CE, McCutcheon, I, Nam, DH, Ronchi, S, Saletti, V, Seizeur, R, Slopis, J, Suñol, M, Vandenbos, F, Varlet, P, Vidaud, D, Watts, C, Tabar, V, Reuss, DE, Kim, SK, Meyronet, D, Mokhtari, K, Salvador, H, Bhat, KP, Eoli, M, Sanson, M, Lasorella, A & Iavarone, A 2019, 'The molecular landscape of glioma in patients with Neurofibromatosis 1', Nature Medicine, vol. 25, no. 1, pp. 176-187. https://doi.org/10.1038/s41591-018-0263-8
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. / The molecular landscape of glioma in patients with Neurofibromatosis 1. In: Nature Medicine. 2019 ; Vol. 25, No. 1. pp. 176-187.
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