A five‐CpG signature of microRNA methylation in non‐G‐CIMP glioblastoma

Summary Aims DNA methylation has been found to regulate microRNAs (miRNAs) expression, but the prognostic value of miRNA‐related DNA methylation aberration remained largely elusive in cancers including glioblastomas (GBMs). This study aimed to investigate the clinical and biological feature of miRNA methylation in GBMs of non‐glioma‐CpG island methylator phenotype (non‐G‐CIMP). Methods Prognostic miRNA methylation loci were analyzed, with TCGA and Rennes cohort as training sets, and independent datasets of GBMs and low‐grade gliomas (LGGs) were obtained as validation sets. Different statistical and bioinformatic analysis and experimental validations were performed to clinically and biologically characterize the signature. Results We identified and validated a risk score based on methylation status of five miRNA‐associated CpGs which could predict survival of GBM patients in a series of training and validation sets. This signature was independent of age and O‐6‐methylguanine‐DNA methyltransferase (MGMT) promoter methylation status. The risk subgroup was associated with angiogenesis and accordingly differential responses to bevacizumab‐contained therapy. MiRNA target analysis and in vitro experiments further confirmed the accuracy of this signature. Conclusion The five‐CpG signature of miRNA methylation was biologically relevant and was of potential prognostic and predictive value for GBMs. It might be of help for improving individualized treatment.