2026-05-22T00:44:39Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/109582024-11-29T21:18:47Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Vaquero-Siguero, Nuria
author
Mu, Quanhua
author
Kroon, Paula
author
Zhang, Ying
author
Galán-Ganga, Marcos
author
Bao, Zhaoshi
author
Wang, Zheng
author
Liu, Hanjie
author
Zhao, Junfei
author
Kim, Hoon
author
Rodriguez-Perales, Sandra
author
Nam, Do-Hyun
author
Verhaak, Roel G W
author
Rabadan, Raul
author
Jiang, Tao
author
Wang, Jiguang
author
Oldrini, Barbara
author
Squatrito, Massimo
author
Sa, Jason K
author
Verhaak, Roel G. W.
funder
Fundación Seve Ballesteros
funder
Asociación Española Contra el Cáncer
funder
National Natural Science Foundation of China
funder
Beijing Municipal Administration of Hospitals
2020-09-03T12:11:49Z
2020-09-03T12:11:49Z
2020
Nat Commun . 2020 ;11(1):3883.
10.1038/s41467-020-17717-0
2041-1723
Nature communications
32753598
http://hdl.handle.net/20.500.12105/10958
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.
eng
PROMOTER METHYLATION
RNA-SEQ
GLIOBLASTOMA
TEMOZOLOMIDE
GENE
BENEFIT
MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas.
journal article
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