Abstract
This study sought to identify promoter-CpG methylation sites that are significantly correlated with overall survival and gene expression regulations in grade II/III gliomas. Fifty-six LGG specimens collected from the University Medical Center Freiburg were profiled using the Methylation 450K array, in a discovery cohort, which was followed by analysis of 471 LGG cases from The Cancer Genome Atlas (TCGA) in a validation cohort. Association between each CpG probe and patient overall survival (OS) was assessed in a Cox model with IDH1/2 mutations using false discovery rate (FDR) < 0.05. Probes were selected based on training association (FDR < 0.05) and being located on promoter regions. Genes were selected based on their correlation of expression and methylation (TCGA dataset only). The prognostic values of the selected genes were determined using univariable Cox model in the TCGA LGG cohort. The correlation of CpG-methylation and gene expression was determined using Pearson Correlation method. 40% of total CpG probes from the Freiburg cohort were found significantly associated with OS of LGG patients in the univariable Cox model, and 53970 CpG probes were validated in the TCGA cohort. 18.3% of 53970 probes are located on promoter regions. 99.7% of transcription start site (TSS) probes show that high promoter methylation levels predict better OS. After incorporating TCGA RNA seq dataset, 2145 CpG probes and 1331 genes were identified, which associate with OS. There was no probe significantly associated with OS in multivariable Cox model with IDH mutation status as co-variate. We identified genes whose promoter methylation regulate their expressions and are associated with favorable LGG patient outcome by controlling cancer cell movement, death and survival, and proliferation. Further studies are underway to identify select genes as therapeutic targets in LGGs, employing both in vitro and in vivo preclinical models.