Abstract
Introduction: Patients with glioblastoma (GBM), one of the most aggressive forms of primary brain tumors, exhibit a wide range of neurologic signs, ranging from headaches to neurologic deficits and cognitive impairment, at first clinical presentation. While such variability is attributed to inter-individual differences in increased intracranial pressure, tumor infiltration, and vascular compromise, a direct association with disease stage, tumor size and location, edema, and necrotic cell death has yet to be established. The lack of specificity of neurologic symptoms often confounds the diagnosis of GBM. It also limits clinicians’ ability to elect treatment regimens that not only prolong survival but also promote symptom management and high quality of life.Methods: To decipher the heterogeneous presentation of neurologic symptoms in GBM, we investigated differences in the molecular makeup of tumors from patients with and without preoperative neurologic deficits. We used the Ivy GAP (Ivy Glioblastoma Atlas Project) database to integrate RNA sequencing data from histologically defined GBM tumor compartments and neurologic examination records for 41 patients. We investigated the association of neurologic deficits with various tumor and patient attributes. We then performed differential gene expression and co-expression network analysis to identify a transcriptional signature specific to neurologic deficits in GBM. Using functional enrichment analysis, we finally provided a comprehensive and detailed characterization of involved pathways and gene interactions.Results: An exploratory investigation of the association of tumor and patient variables with the early development of neurologic deficits in GBM revealed a lack of robust and consistent clinicopathologic prognostic factors. We detected significant differences in the expression of 728 genes (FDR-adjusted p-value ≤ 0.05 and relative fold-change ≥ 1.5), unique to the cellular tumor (CT) anatomical compartment, between neurologic deficit groups. Upregulated differentially expressed genes in CT were enriched for mesenchymal subtype-predictive genes. Applying a systems approach, we then identified co-expressed gene sets that correlated with neurological deficit manifestation (FDR-adjusted p-value < 0.1). Collectively, these findings uncovered significantly enriched immune activation, oxidative stress response, and cytokine-mediated proinflammatory processes.Conclusion: Our study posits that inflammatory processes, as well as a mesenchymal tumor subtype, are implicated in the pathophysiology of preoperative neurologic deficits in GBM.
Highlights
Patients with glioblastoma (GBM), one of the most aggressive forms of primary brain tumors, exhibit a wide range of neurologic signs, ranging from headaches to neurologic deficits and cognitive impairment, at first clinical presentation
Clinical data for our GBM cohort was downloaded from Ivy Glioblastoma Atlas Project (GAP) (Material and Methods; Table 1). patients, with a total of tumors, had available neurologic deficit information
We first investigated the association of neurologic deficits with various prognostic clinical attributes that have been previously shown to predict patient outcome in GBM (Figure 1 and Supplementary Table 1)
Summary
Patients with glioblastoma (GBM), one of the most aggressive forms of primary brain tumors, exhibit a wide range of neurologic signs, ranging from headaches to neurologic deficits and cognitive impairment, at first clinical presentation. GBM patients typically present a spectrum of generalized or focal neurologic symptoms including headaches, partial or generalized seizures, unilateral or bilateral paresis, hemiplegia, ataxia, visual defects, cognitive impairment, and personality changes (Iacob and Dinca, 2009; Burks et al, 2016; Georgakis et al, 2018) These symptoms persist throughout the course of the disease and worsen following surgical resection, severely limiting day-to-day functions, impacting patients’ quality of life, and even influencing survival outcomes (Martinez et al, 2008; Iacob and Dinca, 2009; Georgakis et al, 2018; Lee et al, 2018). This suggests the existence of molecular processes in GBM tumors that contribute to neurological signs
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