Abstract
The outcome of patients with anaplastic gliomas varies considerably depending on single molecular markers, such as mutations of the isocitrate dehydrogenase (IDH) genes, as well as molecular classifications based on epigenetic or genetic profiles. Remarkably, 98% of the RNA within a cell is not translated into proteins. Of those, especially microRNAs (miRNAs) have been shown not only to have a major influence on physiologic processes but also to be deregulated and prognostic in malignancies.To find novel survival markers and treatment options we performed unbiased DNA methylation screens that revealed 12 putative miRNA promoter regions with differential DNA methylation in anaplastic gliomas. Methylation of these candidate regions was validated in different independent patient cohorts revealing a set of miRNA promoter regions with prognostic relevance across data sets. Of those, miR-155 promoter methylation and miR-155 expression were negatively correlated and especially the methylation showed superior correlation with patient survival compared to established biomarkers.Functional examinations in malignant glioma cells further cemented the relevance of miR-155 for tumor cell viability with transient and stable modifications indicating an onco-miRNA activity. MiR-155 also conferred resistance towards alkylating temozolomide and radiotherapy as consequence of nuclear factor (NF)κB activation.Preconditioning glioma cells with an NFκB inhibitor reduced therapy resistance of miR-155 overexpressing cells. These cells resembled tumors with a low methylation of the miR-155 promoter and thus mir-155 or NFκB inhibition may provide treatment options with a special focus on patients with IDH wild type tumors.
Highlights
Anaplastic gliomas of World Health Organization (WHO) grade III are currently subdivided into anaplastic astrocytic and oligodendroglial tumors [1]
The differentially methylated regions (DMRs) data set was derived from a Methyl-CpG immunoprecipitation (MCIp)-based DNA methylation profiling and the promoter set had been previously identified in an H3K4me3 ChIP screen [18]
For all DMR, except the one associated with miR-10b, a high methylation was associated with a longer progression free survival (PFS) and overall survival (OS)
Summary
Anaplastic gliomas of World Health Organization (WHO) grade III are currently subdivided into anaplastic astrocytic and oligodendroglial (and mixed) tumors [1]. The considerable interobserver variation for grading and typing of gliomas [2], the variability of outcomes within the subgroups and a paucity of therapeutically attractive targets derived from this framework have triggered studies suggesting a molecularly-based classification for grade II and III gliomas This histological classification and the underlying mutations in the isocitrate dehydrogenase (IDH) genes 1 and 2 resulting in a glioma CpG island methylator phenotype (GCIMP) [3], 1p/19q co-deletions, as well as mutually exclusive mutations in telomerase reverse transcriptase (TERT) and alpha-thalassemia/ mental retardation syndrome X-linked (ATRX) genes [4, 5] are providing a clinically useful prognostic framework [6]. In a tumor setting the phenotypic effect of miRNAs depends on the function of the inhibited mRNAs
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