Tumor associated seizures in glioblastomas are influenced by survival gene expression in a region-specific manner: A gene expression imaging study
Introduction
Tumor associated seizures (TAS) are both common and debilitating (Hildebrand et al., 2005, Ruda et al., 2012). They are experienced by approximately half of the patients at some point, and about half of those will experience generalized tonic–clonic (GTC) seizures (Chang et al., 2008, van Breemen et al., 2007). TAS as well as the side effects from the use of antiepileptic drugs (AEDs) substantially contribute to morbidity (Hildebrand et al., 2005) and cause a marked decrease in the quality of life in patients with brain tumors (Klein et al., 2003, Moots et al., 1995, van Breemen et al., 2007). As advances in brain tumor treatments increase life expectancy, morbidity from TAS is becoming increasingly burdensome to the patient.
The mechanisms of TAS are incompletely understood and are likely multifactorial (Englot et al., 2012, Ruda et al., 2012, van Breemen et al., 2007). Previous neuroimaging studies demonstrated that tumor size and location play crucial roles in determining seizures related to tumors, and that these neuroimaging characteristics depend on the grade of the tumors. TAS are more likely to occur with smaller tumors in high grade tumors, and vice versa in low grade tumors (Lee et al., 2010). Tumors located in the cortex and in the temporal lobe are more likely to be associated with TAS than deeply seated tumors (Chang et al., 2008, Glantz et al., 1996, Liigant et al., 2001, Lynam et al., 2007, You et al., 2012a, Zaatreh et al., 2003).
Recently, dysregulation of glutamate control through the system xc− transporter (Buckingham et al., 2011) resulting in an increase of extracellular glutamate has been demonstrated to play a critical role in TAS in a mouse model. In human gliomas, increased system xc− expression and decreased expression of the membrane glutamate transporter protein EAAT2, also resulting in increased extracellular glutamate, has been demonstrated in patients with TAS (Yuen et al., 2012). In low grade tumors, abnormal expressions of several genes have been demonstrated from tumor and peritumoral tissue in patients with TAS (Niesen et al., 2013, You et al., 2012b).
Given that both gene expression and neuroimaging features are key characteristics in TAS, there is likely significant interaction between these critical features. In this study, we examine the expressions of 9 genes that are associated with long term survival (Colman et al., 2010). These genes may be of particular interest in TAS as the presence of seizures has been found to be a good prognostic factor in human gliomas (Okumus et al., 2012, Stark et al., 2012). We hypothesize that the influence of gene expression on TAS is regional, e.g. gene expression plays a significant role in determining epileptogenicity in certain regions of the brain whereas it plays little role in other regions where the location of tumor may predominate the determination of epileptogenicity. In regions where TAS is primarily determined by tumor location, we expect little influence of gene expression on TAS, whereas in other regions, gene expression may significantly affect TAS.
Section snippets
Cohort selection
This retrospective study examined patients who underwent surgical evaluation of glioblastomas at the Brigham and Women's Hospital between January 2005 and September 2007. Inclusion criteria are as follows: age ≥18, new diagnosis of brain tumor, supratentorial location, pathologically proven glioblastomas, preoperative acquisition of high quality volumetric MRI scan, and the availability of a gene expression data on the tumor. Because gliomas with an oligodendroglial component are more prone to
Patient population
Seventy-seven patients with glioblastomas were included in this study. Their main clinical characteristics are listed (Table 1). There was no difference in patient age or sex between the two groups. Of patients with TAS, 13 had simple partial seizures, 4 had complex partial seizures, and 15 had generalized seizures.
Tumor size and location
Patients with TAS presented with smaller tumor volumes than patients without TAS (31.1 vs. 58.8 cubic cm, p < 0.001). In patients with TAS, there was a greater number of parietal lobe
Discussion
We examined the effects of glioblastoma neuroimaging and the expression of 9 genes associated with long-term survival in TAS. Expression of OLIG2 was significantly lower in patients with TAS. However, in examining the regional variability, we found that there were significant effects of gene expression on TAS for 2 of the 9 genes.
None of the 9 genes have any previously described seizure-specific mechanisms of action. GPNMB (glycoprotein nonmetastatic melanoma protein B) encodes for a
Conflicts of interest
Kristen Oelschlager and Derek Maetzold are employees of Castle Biosciences. None of the other authors have conflicts of interest.
Acknowledgments
This study was supported by funding from the National Center for Image Guided Therapy (U41 RR019703), National Institutes of Health (P41RR13218), and Castle Biosciences Inc.
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2016, Clinical Neurology and NeurosurgeryCitation Excerpt :In addition, Mulligan et al. [28] suggested no significant associations between lp19q status and the presence or absence of preoperative seizures. However, in a study of 77 cases, Lee et al. [58] performed gene expression imaging to map genetic biomarker expression in brain regions with reference to glioma-associated seizures. These experiments revealed that glioma-related seizures were associated with regions with significantly low expression of OLIG2, which is a basic helix-loop-helix transcription factor that plays crucial roles in oligodendroglial development.