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.
Highlights
3,10 ✉, Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas
By analyzing a large cohort of IDH-wildtype and mutant recurrent gliomas treated with TMZ, we have discovered that a subset of patients carries distinct methylguanine-DNA methyltransferase (MGMT) genomic rearrangements
By analyzing the RNA-seq data of 252 recurrent gliomas, we identified eight different MGMT fusions in seven patients (~3% of all patients, 95% CI, 1.1–5.6%) (Supplementary Data 1 and Supplementary Table 1)
Summary
3,10 ✉, Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. We show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. The O6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of O6-meG lesion by transferring the alkyl group from guanine to a cysteine residue. By analyzing a large cohort of IDH-wildtype and mutant recurrent gliomas treated with TMZ, we have discovered that a subset of patients carries distinct MGMT genomic rearrangements. These MGMT alterations lead to MGMT overexpression, independently from changes in its promoter methylation, and contribute to TMZ resistance both in vitro and in vivo
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