MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

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 () and Massimo Squatrito ()
Additional contact information
Barbara Oldrini: Seve Ballesteros Foundation Brain Tumor Group, Molecular Oncology Programme, Spanish National Cancer Research Center, CNIO
Nuria Vaquero-Siguero: Seve Ballesteros Foundation Brain Tumor Group, Molecular Oncology Programme, Spanish National Cancer Research Center, CNIO
Quanhua Mu: Division of Life Science, Department of Chemical and Biological Engineering, Center of Systems Biology and Human Health and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology
Paula Kroon: Seve Ballesteros Foundation Brain Tumor Group, Molecular Oncology Programme, Spanish National Cancer Research Center, CNIO
Ying Zhang: Beijing Neurosurgical Institute, Capital Medical University
Marcos Galán-Ganga: Seve Ballesteros Foundation Brain Tumor Group, Molecular Oncology Programme, Spanish National Cancer Research Center, CNIO
Zhaoshi Bao: Division of Life Science, Department of Chemical and Biological Engineering, Center of Systems Biology and Human Health and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology
Zheng Wang: Beijing Neurosurgical Institute, Capital Medical University
Hanjie Liu: Beijing Neurosurgical Institute, Capital Medical University
Jason K. Sa: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine
Junfei Zhao: Columbia University
Hoon Kim: The Jackson Laboratory for Genomic Medicine
Sandra Rodriguez-Perales: Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Center, CNIO
Do-Hyun Nam: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine
Roel G. W. Verhaak: The Jackson Laboratory for Genomic Medicine
Raul Rabadan: Columbia University
Tao Jiang: Beijing Neurosurgical Institute, Capital Medical University
Jiguang Wang: Division of Life Science, Department of Chemical and Biological Engineering, Center of Systems Biology and Human Health and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology
Massimo Squatrito: Seve Ballesteros Foundation Brain Tumor Group, Molecular Oncology Programme, Spanish National Cancer Research Center, CNIO

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17717-0

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