MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas.

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.

• Authors: Barbara Oldrini, Nuria Vaquero-Siguero, Quanhua Mu, Paula Kroon, Ying Zhang, Marcos Galán-Ganga, Zhaoshi Bao, Zheng Wang, Hanjie Liu, Jason K Sa, Junfei Zhao, Hoon Kim, Sandra Rodriguez-Perales, Do-Hyun Nam, Roel G W Verhaak, Raul Rabadan, Tao Jiang, Jiguang Wang, Massimo Squatrito
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 3883 (08 04 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32753598 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Adducts
• Tumor Suppressor Proteins
• DNA Modification Methylases
• MGMT protein, human
• DNA Repair Enzymes
• Temozolomide

Topics

• Adolescent
• Adult
• Aged
• Animals
• Brain Neoplasms (drug therapy, genetics)
• Cell Line, Tumor
• DNA Adducts (drug effects, metabolism)
• DNA Methylation
• DNA Modification Methylases (genetics, metabolism)
• DNA Repair Enzymes (genetics, metabolism)
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Gene Rearrangement
• Glioma (drug therapy, genetics)
• Humans
• Male
• Mice
• Middle Aged
• Neoplasm Recurrence, Local (genetics, prevention & control)
• Promoter Regions, Genetic (genetics)
• RNA-Seq
• Temozolomide (pharmacology, therapeutic use)
• Tumor Suppressor Proteins (genetics, metabolism)
• Up-Regulation
• Whole Genome Sequencing
• Xenograft Model Antitumor Assays
• Young Adult