TY - JOUR
T1 - MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas
AU - Oldrini, Barbara
AU - Vaquero-Siguero, Nuria
AU - Mu, Quanhua
AU - Kroon, Paula
AU - Zhang, Ying
AU - Galán-Ganga, Marcos
AU - Bao, Zhaoshi
AU - Wang, Zheng
AU - Liu, Hanjie
AU - Sa, Jason K.
AU - Zhao, Junfei
AU - Kim, Hoon
AU - Rodriguez-Perales, Sandra
AU - Nam, Do-Hyun
AU - Verhaak, Roel G. W.
AU - Rabadan, Raul
AU - Jiang, Tao
AU - Wang, Jiguang
AU - Squatrito, Massimo
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85089035003&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/32753598
U2 - https://doi.org/10.1038/s41467-020-17717-0
DO - https://doi.org/10.1038/s41467-020-17717-0
M3 - Article
C2 - 32753598
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3883
ER -