Document Type
Article
Publication Date
8-4-2020
Keywords
JGM, JAXCC
JAX Source
Nat Commun 2020 Aug 4; 11(1):3883
Volume
11
Issue
1
First Page
3883
Last Page
3883
ISSN
2041-1723
PMID
32753598
DOI
https://doi.org/10.1038/s41467-020-17717-0
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.
Recommended Citation
Oldrini B,
Vaquero-Siguero N,
Mu Q,
Kroon P,
Zhang Y,
Galán-Ganga M,
Bao Z,
Wang Z,
Liu H,
Sa J,
Zhao J,
Kim H,
Rodriguez-Perales S,
Nam D,
Verhaak R,
Rabadan R,
Jiang T,
Wang J,
Squatrito M.
MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas. Nat Commun 2020 Aug 4; 11(1):3883
Comments
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