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67th Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Korean Neurosurgical Society (KNS)

German Society of Neurosurgery (DGNC)

12 - 15 June 2016, Frankfurt am Main

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Impact of hypoxia-regulated genes in glioblastoma stem cells on patient survival

Meeting Abstract

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  • Philip Dao Trong - Neurochirurgische Universitätsklinik Heidelberg, Abteilung für Experimentelle Neurochirurgie, Germany
  • Rolf Warta - Neurochirurgische Universitätsklinik Heidelberg, Abteilung für Experimentelle Neurochirurgie, Germany
  • Christoph Geisenberger - Neurochirurgische Universitätsklinik Heidelberg, Abteilung für Experimentelle Neurochirurgie, Germany
  • Andreas Mock - Neurochirurgische Universitätsklinik Heidelberg, Abteilung für Experimentelle Neurochirurgie, Germany
  • Andreas Unterberg - Neurochirurgische Universitätsklinik Heidelberg, Abteilung für Experimentelle Neurochirurgie, Germany
  • Christel Herold-Mende - Neurochirurgische Universitätsklinik Heidelberg, Abteilung für Experimentelle Neurochirurgie, Germany

Deutsche Gesellschaft für Neurochirurgie. 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS). Frankfurt am Main, 12.-15.06.2016. Düsseldorf: German Medical Science GMS Publishing House; 2016. DocP 100

doi: 10.3205/16dgnc475, urn:nbn:de:0183-16dgnc4758

Published: June 8, 2016

© 2016 Trong et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

Text

Objective: Low oxygen tension (hypoxia) has shown to play a major role in gliomagenesis and seems to maintain the glioma stem cell (GSC) phenotype and promotes resistance to therapy. It has also become evident that IDH status plays a crucial role in the prognosis and treatment of glioma patients. Since its role in glioblastoma stem cell biology especially under low oxygen tension has not yet been sufficiently understood, the following study has been conducted.

Method: Eight well characterized IDH1 mutated (mut) and wildtype (wt) GSC lines were grown under serum-free normoxic (20%) and hypoxic (1.5%) conditions to harvest mRNA after 72 hrs. Gene expression analyses were performed on a two-color Agilent Gene Expression Microarray. Differentially expressed genes were defined by significant up-regulation by two fold or down-regulation by half after non parametric testing (Mann-Whitney U-Test). Possible survival associations of candidate genes were analyzed using the expression data from the GBM dataset of ‘The Cancer Genome Atlas’ (TCGA).

Results: Most interestingly, differentially expressed genes under hypoxia do not overlap between IDH1mut and wt GSC. Additionally, only 2 genes were up-regulated in IDH1mut GSC (GLUT1, TMEM45A), while 137 genes were up-regulated in IDH1wt GSC (p<0.05). We further correlated these candidates with expression levels of the TCGA GBM study cohort and identified ten genes whose overexpression showed a significant survival disadvantage (RPL37, KLF6, PPP1R15A, CCNL1, RIOK3, JMJD6, LAMA5, HERPUD1, INSIG1, ANG) underlining its possible role in tumorigenesis. Furthermore, multivariate analysis adjusted for age and MGMT methylation status revealed that patient outcome of INSIG1 and ANG expression is dependent on the MGMT methylation status suggesting a not yet characterized mechanistic link. Further genes belong to pathways such as p53/MDM2, oxidative stress (RBL37) and hypoxia (JMJD6) or have been described as cancer promoting in other tumor entities (CCNL1).

Conclusions: Expression profiles of IDH1wt GBM stem cells seem to be more sensitive to hypoxia-induced changes than those of IDH1mut GBM stem cells. Analysis of gene expression with the TCGA GBM patient dataset revealed ten candidate genes significantly correlated with patient survival.