O9.06 * PROGNOSTIC RELEVANCE AND ONCOGENIC CORRELATES OF EPILEPSY IN GLIOBLASTOMA PATIENTS

Abstract

BACKGROUND: In 30-40% of glioblastoma patients, the disease present with an epileptic seizure. Some studies suggest that tumor-associated epilepsy influences the survival of glioblastoma patients, possibly due to early diagnosis or the tumors' biology. However, the in vivo mechanisms underlying the suggested prognostic effect of epilepsy in glioblastoma patients are still unclear. METHODS: In a retrospective cohort study, we investigated the effect of epilepsy on survival of 230 glioblastoma patients using multivariate Weibull analysis. Gene set enrichment analyses defined the transcriptional effects of epilepsy and anti-epileptic drug treatments using gene expression microarrays of 50 fresh frozen surgical specimens. Protein expression was analyzed using immunohistochemistry on tissue microarrays containing surgical specimens of 230 patients. In vitro reporter gene assays, western blotting, kinase assays and immunocytochemistry experiments were performed to confirm our findings. RESULTS: Epilepsy is an independent prognostic factor in glioblastoma patients (HR 0.71, 95%CI: 0.53 - 0.96, p = 0.024), irrespective of other clinical characteristics. The epilepsy subgroup displayed a distinct gene expression pattern, with a significant downregulation of, notably, the oncologically relevant NF-κB, C/EBPβ and STAT3, -5A and -5B transcription factor associated genes. At a protein level, a significant downregulation of phosphorylated STAT3 and C/EBPβ expression, but not of phosphorylated STAT5b or NF-κB p65, was confirmed in the surgical samples. In addition, a significant repression of NF-κB was observed in the patients who were treated with the anti-epileptic drug valproic acid (VPA) prior to their surgery. In vitro, VPA inhibited NF-κB transcriptional activity and was shown to increase acetylated histone H3 and H4 expression. CONCLUSION: Glioblastoma patients with tumor-associated epilepsy form a distinct subgroup with a favorable prognosis and a distinct gene expression pattern involving downregulation of oncologically relevant pathways. The anti-epileptic drug VPA downregulates NF-κB signaling, which might, as suggested in recent literature, contribute to a longer survival of glioblastoma patients.