MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas. Oldrini, B., Vaquero-Siguero, N., Mu, Q., Kroon, P., Zhang, Y., Galán-Ganga, M., Bao, Z., Wang, Z., Liu, H., Sa, J. K, Zhao, J., Kim, H., Rodriguez-Perales, S., Nam, D., Verhaak, R. G W, Rabadan, R., Jiang, T., Wang, J., & Squatrito, M. Nat. Commun., 11(1):3883, August, 2020.

Paper doi abstract bibtex

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.

@ARTICLE{Oldrini2020-fp,
  title    = "{MGMT} genomic rearrangements contribute to chemotherapy
              resistance in gliomas",
  author   = "Oldrini, Barbara and Vaquero-Siguero, Nuria and Mu, Quanhua and
              Kroon, Paula and Zhang, Ying and Gal{\'a}n-Ganga, Marcos and Bao,
              Zhaoshi and Wang, Zheng and Liu, Hanjie and Sa, Jason K and Zhao,
              Junfei and Kim, Hoon and Rodriguez-Perales, Sandra and Nam,
              Do-Hyun and Verhaak, Roel G W and Rabadan, Raul and Jiang, Tao
              and Wang, Jiguang and Squatrito, Massimo",
  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.",
  journal  = "Nat. Commun.",
  volume   =  11,
  number   =  1,
  pages    = "3883",
  month    =  aug,
  year     =  2020,
  url      = "http://dx.doi.org/10.1038/s41467-020-17717-0",
  language = "en",
  issn     = "2041-1723",
  pmid     = "32753598",
  doi      = "10.1038/s41467-020-17717-0",
  pmc      = "PMC7403430"
}

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