MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

• DOI: 10.1038/s41467-020-17717-0
• Publication Date: 2020-08-04T10:03:35Z
• Authors: Barbara Oldrini; Nuria Vaquero-Sig...; Quanhua Mu; Paula Kroon; Ying Zhang; Marcos Galán-Ganga; Zhaoshi Bao; Zheng Wang; Hanjie Liu; Jason K. Sa; Junfei Zhao; Hoon Kim; Sandra Rodriguez-...; Do-Hyun Nam; Roel G. W. Verhaak; Raul Rabadan; Tao Jiang; Jiguang Wang; Massimo Squatrito
• Keywords: Temozolomide; O-6-methylguanine-DNA methyltransferase; DNA methyltransferase

Abstract Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) responsible direct repair main TMZ-induced toxic DNA adduct, O6-Methylguanine lesion. MGMT promoter hypermethylation currently only known biomarker TMZ response patients. Here we show that subset recurrent gliomas carries genomic rearrangements lead to overexpression, independently from changes its methylation. By leveraging CRISPR/Cas9 technology generated some these glioma cells demonstrated contribute resistance both vitro vivo. Lastly, showed such fusions can be detected tumor-derived exosomes could potentially represent early detection marker tumor recurrence treated TMZ.