Abstract
Whether patients with glioblastoma that contacts the ventricular-subventricular zone stem cell niche (VSVZ + GBM) have a distinct survival profile from VSVZ − GBM patients independent of other known predictors or molecular profiles is unclear. Using multivariate Cox analysis to adjust survival for widely-accepted predictors, hazard ratios (HRs) for overall (OS) and progression free (PFS) survival between VSVZ + GBM and VSVZ − GBM patients were calculated in 170 single-institution patients and 254 patients included in both The Cancer Genome (TCGA) and Imaging (TCIA) atlases. An adjusted, multivariable analysis revealed that VSVZ contact was independently associated with decreased survival in both datasets. TCGA molecular data analyses revealed that VSVZ contact by GBM was independent of mutational, DNA methylation, gene expression, and protein expression signatures in the bulk tumor. Therefore, while survival of GBM patients is independently stratified by VSVZ contact, with VSVZ + GBM patients displaying a poor prognosis, the VSVZ + GBMs do not possess a distinct molecular signature at the bulk sample level. Focused examination of the interplay between the VSVZ microenvironment and subsets of GBM cells proximal to this region is warranted.
Highlights
To address this critical gap in our understanding of the clinical and molecular differences in VSVZ + GBMs and VSVZ − GBMs, the association between patient survival and glioblastoma contact with the VSVZ was rigorously and comprehensively tested in two independent patient datasets
Both univariate log-rank (Mantel–Cox) and multivariate Cox proportional hazards regression survival analyses were performed to test the impact of VSVZ contact on survival, and the data are reported as hazard ratios (HRs) with 95% confidence intervals (CIs)
Our survival analysis of VSVZ + GBMs and VSVZ − GBMs was adjusted for universally-accepted predictors of survival in GBM patients, including patient performance status (i.e., KPS), tumor volume, and extent of resection, which are potential confounders of an analysis focused on this region
Summary
Their age, preoperative Karnofsky performance status score (KPS), whether they received postoperative radiotherapy and temozolomide and completed the Stupp protocol regimen, their GBM molecular status (i.e., MGMT promoter methylation and IDH1/2 mutation), and overall (OS) and progression free (PFS) survivals were collected Another 254 patients from The Cancer Imaging Archive (TCIA)[19] with contrasted brain imaging and corresponding OS data in The Cancer Genome Atlas (TCGA-GBM) database were identified (Table S1)[20]. Survival time points were censored at the latest time of follow-up if patients were alive or their living status was unknown (for OS) or at the last time of intracranial imaging if they had no evidence of tumor progression/recurrence (PFS) Both univariate log-rank (Mantel–Cox) and multivariate Cox proportional hazards regression survival analyses were performed to test the impact of VSVZ contact on survival, and the data are reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Results of these analyses on other datasets are available upon request
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