Comparative Transcriptome Analysis Identifies Target Genes for Treatment of IDH Wild-type Lower-grade Gliomas

Objective: Isocitrate dehydrogenase 1/2 (IDH 1/2) mutations define a group of low-grade gliomas (LGGs) that display more favorable prognosis compared with LGGs without them. Although IDH wild-type (IDHwt) LGGs are classified as low-grade, they almost invariably progress to higher grades and rarely respond to aggressive treatment regimes. Here, we employed a comparative transcriptomic approach to identify key genes that could significantly contribute to the aggressive progression of IDHwt LGGs.
Methods: Using The Cancer Genome Atlas LGG cohort data and weighted gene coexpression network analysis methodology, we identified modules that correlated significantly with clinical features. We focused on modules that correlated with telomerase reverse transcriptase (TERT) promoter mutation status, as TERT promoter mutations are shared between glioblastomas and oligodendrogliomas, however, with two opposite prognostic outcomes. We selected module pathways shared between IDH mutant (IDHmt) and IDHwt LGGs and identified genes that were differentially expressed between the two groups.
Results: Several synaptic proteins are down-regulated in IDHwt compared with IDHmt, while GNG12 and VIPR2 are up-regulated. Finally, we identified known drugs that could target many of those genes and therefore could be tested against IDHwt LGGs.
Conclusion: Targeting of multiple candidate genes identified in this study could provide novel approaches toward the treatment of IDHwt LGGs.