MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas.
Adolescent
Adult
Aged
Animals
Brain Neoplasms
/ drug therapy
Cell Line, Tumor
DNA Adducts
/ drug effects
DNA Methylation
DNA Modification Methylases
/ genetics
DNA Repair Enzymes
/ genetics
Drug Resistance, Neoplasm
/ genetics
Female
Gene Expression Regulation, Neoplastic
Gene Rearrangement
Glioma
/ drug therapy
Humans
Male
Mice
Middle Aged
Neoplasm Recurrence, Local
/ genetics
Promoter Regions, Genetic
/ genetics
RNA-Seq
Temozolomide
/ pharmacology
Tumor Suppressor Proteins
/ genetics
Up-Regulation
Whole Genome Sequencing
Xenograft Model Antitumor Assays
Young Adult
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 08 2020
04 08 2020
Historique:
received:
24
08
2019
accepted:
16
07
2020
entrez:
6
8
2020
pubmed:
6
8
2020
medline:
22
9
2020
Statut:
epublish
Résumé
Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.
Identifiants
pubmed: 32753598
doi: 10.1038/s41467-020-17717-0
pii: 10.1038/s41467-020-17717-0
pmc: PMC7403430
doi:
Substances chimiques
DNA Adducts
0
Tumor Suppressor Proteins
0
DNA Modification Methylases
EC 2.1.1.-
MGMT protein, human
EC 2.1.1.63
DNA Repair Enzymes
EC 6.5.1.-
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3883Références
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