MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas.
Nat Commun
; 11(1): 3883, 2020 08 04.
Article
in En
| MEDLINE
| ID: mdl-32753598
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Neoplasms
/
DNA Modification Methylases
/
Gene Rearrangement
/
Drug Resistance, Neoplasm
/
Tumor Suppressor Proteins
/
DNA Repair Enzymes
/
Temozolomide
/
Glioma
/
Neoplasm Recurrence, Local
Type of study:
Observational_studies
/
Screening_studies
Limits:
Adolescent
/
Adult
/
Aged
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2020
Type:
Article
Affiliation country:
Spain