TMIC-09. EXPRESSION ANALYSIS OF IDH1 WILD-TYPE AND MUTANT GLIOMA STEM CELLS UNDER HYPOXIA IDENTIFIES NOVEL SURVIVAL-ASSOCIATED GENES IN GLIOBLASTOMA PATIENTS

The hypoxic microenvironment seems to drive the glioma stem cell (GSC) phenotype and to promote resistance to radiation and differentiating agents. The IDH1 status has shown to play a crucial role in the prognosis and treatment of glioma patients. Most studies analyzing the behavior of IDH mutated (mut) and wildtype (wt) glioma cells or tumor tissue in different oxygen tensions have synthetically introduced the IDH1 mutation into common cell lines (e.g. U87MG, U251, A172) leading to inconsistent results. In our experiments we were able to isolate GSC from IDH1mut and –wt tumor tissue. Taking into account the natural genetic background, we performed expression analysis with IDH1mut and -wt GSC lines which were grown 72h under normoxic (20%) and hypoxic (1.5%) culture conditions. Possible survival associations of candidate genes were tested using the expression data from the GBM dataset of ‘The Cancer Genome Atlas’ (TCGA). The differential mRNA expression analyses revealed that strongest expression changes were seen in IDH1wt GSCs (34 genes vs. 0 genes). Further analyses of these 34 genes isolated three differentially overexpressed candidate genes in hypoxia (P4HA1, PPP1R15A and INSIG1) which showed a significant survival disadvantage in GBM IDHwt patients of the TCGA study population. Taken together this study suggests, that IDH1mut GSCs do not seem to react to hypoxia on the transcriptional level. In contrast, IDH1wt GSCs regulate 34 genes, of which three show a significant survival correlation in GBM IDHwt patients.