期刊
CNS NEUROSCIENCE & THERAPEUTICS
卷 24, 期 3, 页码 167-177出版社
WILEY
DOI: 10.1111/cns.12786
关键词
bevacizumab; DNA methylation; glioblastomas; prognostication; risk-score signature
资金
- National Natural Science Foundation of China [81402049, 81471266]
- Brittany Region (France) et the FEDER (Europe)
AimsWe aimed to identify a clinically useful biomarker using DNA methylation-based information to optimize individual treatment of patients with glioblastoma (GBM). MethodsA six-CpG panel was identified by incorporating genome-wide DNA methylation data and clinical information of three distinct discovery sets and was combined using a risk-score model. Different validation sets of GBMs and lower-grade gliomas and different statistical methods were implemented for prognostic evaluation. An integrative analysis of multidimensional TCGA data was performed to molecularly characterize different risk tumors. ResultsThe six-CpG risk-score signature robustly predicted overall survival (OS) in all discovery and validation cohorts and in a treatment-independent manner. It also predicted progression-free survival (PFS) in available patients. The multimarker epigenetic signature was demonstrated as an independent prognosticator and had better performance than known molecular indicators such as glioma-CpG island methylator phenotype (G-CIMP) and proneural subtype. The defined risk subgroups were molecularly distinct; high-risk tumors were biologically more aggressive with concordant activation of proangiogenic signaling at multimolecular levels. Accordingly, we observed better OS benefits of bevacizumab-contained therapy to high-risk patients in independent sets, supporting its implication in guiding usage of antiangiogenic therapy. Finally, the six-CpG signature refined the risk classification based on G-CIMP and MGMT methylation status. ConclusionsThe novel six-CpG signature is a robust and independent prognostic indicator for GBMs and is of promising value to improve personalized management.
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