Novel epigenetic signature of DNA damage response genes for prognostication and immunophenotype of non-G-CIMP glioblastomas

Abstract Background Dysregulation and dysfunction of DNA damage response (DDR) have prognostic and predictive implications for glioblastomas (GBMs) without glioma-CpGs island methylator phenotype (G-CIMP); mathematical modeling based on DNA methylation abnormality in DDR genes may serve as clinically useful biomarkers. Methods Independent cohorts of non-G-CIMP GBMs and IDH wild type (wt) lower-grade gliomas (LGGs) from local and public databases were included for discovery and validation of a multimarker signature, combined using a RISK score model. Different bioinformatic and functional experiments were performed for biological validation. Results By analyzing DNA methylation microarray data of DDR genes, we totally identified five CpGs, each of which was significantly correlated with overall survival (OS) of non-G-CIMP GBMs, independent of age, treatments and the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status. A RISK score signature of the 5 CpGs was constructed and validated to powerfully and independently prognosticate prognosis in non-G-CIMP GBMs. It also showed good discriminating value in stratified cohorts by patient age and MGMT methylation status. Bioinformatic analysis revealed a close correlation of the DDR epigenetic signature to distinct immunophenotypes of non-G-CIMP GBMs. Functional studies showed that NSUN5, epigenetically regulated by one identified CpGs, exhibited tumor-suppressor characteristics but may have immunosuppressive implications and confer TMZ resistance to GBM cells. Conclusions The epigenetic signature of DDR genes might be of promising value for refining current prognostic classification of non-G-CIMP GBMs, and its potential links to distinct immunophenotypes make it a promising biomarker candidate in the coming era of cancer immunotherapy.