RARRES2 is Downregulated in Isocitrate Dehydrogenase 1 Mutant Glioma Patients and Served as an Unfavorable Prognostic Factor of Glioma

BACKGROUND: Mutations in isocitrate dehydrogenase 1 (IDH1) induce extensive transcriptional alterations to promote glioma development. However, IDH1 mutation contributes the better clinical outcomes of glioma. Further -nderstanding the transcriptional and DNA methylation changes mediated by IDH1 mutation will provide new therapeutic targets for glioma.METHODS: Public glioma cohorts were collected and processed using R software. The transcriptional changes mediated by IDH1 mutation were determined and presented using heatmap. The differentially expressed genes in IDH1 mutant glioma were overlapped using TBtools. The prog-nostic effects of IDH1 regulated genes were determined by Kaplan-Meier survival analysis.RESULTS: Retinoic acid receptor responder 2 (RARRES2) was upregulated in IDH1 wild type lower-grade glioma (LGG) patients, and higher expression levels of RARRES2 were associated with worse clinical outcomes of LGG. Moreover, IDH1 wild type LGG patients with higher expression levels of RARRES2 had even worse overall survival. Compared with LGG, RARRES2 was upregulated in grade IV glioma (glioblastoma multiforme, GBM). Also, RARRES2 represented an unfavorable prognostic factor of glioma. In GBM, RARRES2 was also associated with IDH1 mutation. In both LGG and GBM, IDH1 mutation induced extensive DNA hypermethylation, and more than half genes that were downregulated in IDH1 mutant glioma werecontributed by DNA hypermethylation. RARRES2 was also hypermethylated in IDH1 mutant LGG or GBM patients. Furthermore, RARRES2 hypomethylation was an unfavor-able prognostic factor in patients with LGG.CONCLUSIONS: RARRES2 was downregulated by IDH1 mutation and served as an unfavorable prognostic factor in glioma.