Novel gene expression patterns associated with progression and adverse outcome in high-grade gliomas

Abstract

1562 Background: The objective of this study was to identify genes and pathways deregulated within high grade gliomas, specifically with regards to survival, histological grade and pathological features. Previous reports have provided a list of individual genes associated with progression and outcome, the present study extends these findings by identifying larger molecular pathways associated with adverse outcome and glioma progression. Methods: Thirty-five prospectively-collected high-grade glioma specimens [WHO grade III/IV (AA) and IV/IV (GBM), respectively] were “snap frozen” at time of surgical resection under an IRB-approved protocol. Specimens included in this study were found to represent at least 95% tumor. Isolated mRNA was converted to cDNA and subsequently hybridized to HG-U133A arrays (Affymetrix). Classification, prediction, differential expression and co-expression were analyzed using Gene Pattern. Pathway information was analyzed using Gene Set Enrichment Analysis (GSEA). Results: We found that GBMs were enriched with pathways related to immune and inflammatory response, as compared to AA. Many of these pathways consist of immune cell surface proteins. AA was enriched with pathways associated with cell growth and survival. The comparison between de novo and progressive GBM resembled that of the GBM versus AA comparison. De novo GBMs were enriched with pathways involved in antigen-specific immune response. The AKT pathway was the highest ranked pathway enriched in the progressive GBM. Further, we have identified specific molecular pathways that are involved in adverse clinical outcome in high-grade gliomas. We also have identified specific molecular pathways that may play a vital role in radiation resistance. Conclusions: It seems as though GBM, especially those which are de novo, display characteristics of stress, immune and inflammatory response. The progressive GBMs and AAs seem to be typified by deregulation of growth and survival pathways, such as AKT and RAS. This may be a result of a general progression or due to different molecular etiology. We will further describe cellular pathways associated with adverse outcome and radiation resistance in high-grade gliomas. No significant financial relationships to disclose.