The molecular landscape of glioma in patients with Neurofibromatosis 1.
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
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
16
04
2018
accepted:
17
10
2018
pubmed:
12
12
2018
medline:
11
5
2019
entrez:
12
12
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30531922
doi: 10.1038/s41591-018-0263-8
pii: 10.1038/s41591-018-0263-8
pmc: PMC6857804
mid: NIHMS1057272
doi:
Substances chimiques
Antigens, Neoplasm
0
NF1 protein, human
0
Neurofibromin 1
0
ATRX protein, human
EC 3.6.4.12
X-linked Nuclear Protein
EC 3.6.4.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
176-187Subventions
Organisme : NCI NIH HHS
ID : R01 CA127643
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA085628
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190891
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA101644
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA193313
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS061776
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239698
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA179044
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA131126
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA178546
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239721
Pays : United States
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