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"
}