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MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

Author

Listed:
  • 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
    Beijing Neurosurgical Institute, Capital Medical University)

  • 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
    Korea University College 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)

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.

Suggested Citation

  • 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-P, 2020. "MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17717-0
    DOI: 10.1038/s41467-020-17717-0
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    Cited by:

    1. Yatian Li & Zhenyue Gao & Yuhong Wang & Bo Pang & Binbin Zhang & Ruxin Hu & Yuqing Wang & Chao Liu & Xuebin Zhang & Jingxuan Yang & Mei Mei & Yongzhi Wang & Xuan Zhou & Min Li & Yu Ren, 2023. "Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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