Genome-wide DNA methylation analysis identifies potent CpG signature for temzolomide response in non-G-CIMP glioblastomas with unmethylated MGMT promoter: MGMT-dependent roles of GPR81 - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue CNS Neuroscience & Therapeutics Année : 2023

Genome-wide DNA methylation analysis identifies potent CpG signature for temzolomide response in non-G-CIMP glioblastomas with unmethylated MGMT promoter: MGMT-dependent roles of GPR81

Yu-Hong Wang
Jingjing Huang
Shuai Lin
Guo-Chao Mao
  • Fonction : Auteur
Wan-Jun Yan
Hui-Zi Wu
Ya-Long He
Fangfang Liu
Hua-Feng Kang
An-An Yin
Shu-Qun Zhang

Résumé

Purposes - To identify potent DNA methylation candidates that could predict response to temozolomide (TMZ) in glioblastomas (GBMs) that do not have glioma-CpGs island methylator phenotype (G-CIMP) but have an unmethylated promoter of O-6-methylguanine-DNA methyltransferase (unMGMT). Methods - The discovery-validation approach was planned incorporating a series of G-CIMP-/unMGMT GBM cohorts with DNA methylation microarray data and clinical information, to construct multi-CpG prediction models. Different bioinformatic and experimental analyses were performed for biological exploration. Results - By analyzing discovery sets with radiotherapy (RT) plus TMZ versus RT alone, we identified a panel of 64 TMZ efficacy-related CpGs, from which a 10-CpG risk signature was further constructed. Both the 64-CpG panel and the 10-CpG risk signature were validated showing significant correlations with overall survival of G-CIMP-/unMGMT GBMs when treated with RT/TMZ, rather than RT alone. The 10-CpG risk signature was further observed for aiding TMZ choice by distinguishing differential outcomes to RT/TMZ versus RT within each risk subgroup. Functional studies on GPR81, the gene harboring one of the 10 CpGs, indicated its distinct impacts on TMZ resistance in GBM cells, which may be dependent on the status of MGMT expression. Conclusions - The 64 TMZ efficacy-related CpGs and in particular the 10-CpG risk signature may serve as promising predictive biomarker candidates for guiding optimal usage of TMZ in G-CIMP-/unMGMT GBMs.

Dates et versions

hal-04284288 , version 1 (14-11-2023)

Identifiants

Citer

Bao-Bao Liang, Yu-Hong Wang, Jingjing Huang, Shuai Lin, Guo-Chao Mao, et al.. Genome-wide DNA methylation analysis identifies potent CpG signature for temzolomide response in non-G-CIMP glioblastomas with unmethylated MGMT promoter: MGMT-dependent roles of GPR81. CNS Neuroscience & Therapeutics, 2023, ⟨10.1111/cns.14465⟩. ⟨hal-04284288⟩
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