Rxivist logo

MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

By 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

Posted 11 Mar 2020
bioRxiv DOI: 10.1101/2020.03.10.985226 (published DOI: 10.1038/s41467-020-17717-0)

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.

Download data

  • Downloaded 253 times
  • Download rankings, all-time:
    • Site-wide: 71,146 out of 106,159
    • In cancer biology: 2,384 out of 3,707
  • Year to date:
    • Site-wide: 23,578 out of 106,159
  • Since beginning of last month:
    • Site-wide: 32,108 out of 106,159

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News