Ventricular-Subventricular Zone Contact by Glioblastoma is Not Associated with Molecular Signatures in Bulk Tumor Data

Mistry, Akshitkumar M.; Wooten, David J.; Davis, L. Taylor; Mobley, Bret C.; Quaranta, Vito; Ihrie, Rebecca A.

doi:10.1038/s41598-018-37734-w

Cited by 29 publications

(22 citation statements)

References 51 publications

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“…Using the same dataset however and our clinician-friendly definition of SVZ contact based on the enhancing tumor core rather than a complex image analysis algorithm, we did not find any association between molecular subtype and SVZ contact in this same TCGA/TCIA and our cohorts. Our results are in line with a recent report of similar analyses to explore this hypothesis with the TCGA/TCIA dataset [46].…”

Section: Discussionsupporting

confidence: 93%

“…In a large institutional cohort (n = 647) and a cohort from the TCIA/TCGA repository (n = 222), we show that contact between the gadolinium-enhancing, T1-weighted imaging core component of glioblastomas and the SVZ of the brain is an adverse prognostic factor, independent of other known prognostic factors age, preoperative KPS, surgery type and postoperative treatment [37]. These results considerably strengthen the associations found by others, who had explored this hypothesis with univariable survival models [14, 16, 17, 38–40] or smaller to mid-size cohorts [17, 18, 41–46], and may help define the prognosis of individual patients based on their preoperative MR imaging. A meta-analysis of these published series also showed a significant adverse prognostic effect of SVZ contact in glioblastoma patients [47], but these analyses were not corrected for the effects of other (clinical) factors, due to unavailable individual patient data.…”

Section: Discussionsupporting

confidence: 64%

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Adverse prognosis of glioblastoma contacting the subventricular zone: Biological correlates

et al. 2019

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IntroductionThe subventricular zone (SVZ) in the brain is associated with gliomagenesis and resistance to treatment in glioblastoma. In this study, we investigate the prognostic role and biological characteristics of subventricular zone (SVZ) involvement in glioblastoma.MethodsWe analyzed T1-weighted, gadolinium-enhanced MR images of a retrospective cohort of 647 primary glioblastoma patients diagnosed between 2005–2013, and performed a multivariable Cox regression analysis to adjust the prognostic effect of SVZ involvement for clinical patient- and tumor-related factors. Protein expression patterns of a.o. markers of neural stem cellness (CD133 and GFAP-δ) and (epithelial-) mesenchymal transition (NF-κB, C/EBP-β and STAT3) were determined with immunohistochemistry on tissue microarrays containing 220 of the tumors. Molecular classification and mRNA expression-based gene set enrichment analyses, miRNA expression and SNP copy number analyses were performed on fresh frozen tissue obtained from 76 tumors. Confirmatory analyses were performed on glioblastoma TCGA/TCIA data.ResultsInvolvement of the SVZ was a significant adverse prognostic factor in glioblastoma, independent of age, KPS, surgery type and postoperative treatment. Tumor volume and postoperative complications did not explain this prognostic effect. SVZ contact was associated with increased nuclear expression of the (epithelial-) mesenchymal transition markers C/EBP-β and phospho-STAT3. SVZ contact was not associated with molecular subtype, distinct gene expression patterns, or markers of stem cellness. Our main findings were confirmed in a cohort of 229 TCGA/TCIA glioblastomas.ConclusionIn conclusion, involvement of the SVZ is an independent prognostic factor in glioblastoma, and associates with increased expression of key markers of (epithelial-) mesenchymal transformation, but does not correlate with stem cellness, molecular subtype, or specific (mi)RNA expression patterns.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 64%

Adverse prognosis of glioblastoma contacting the subventricular zone: Biological correlates

et al. 2019

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“…This finding mirrors the results of a prior study in GBMs that reported that SVZ involvement, though associated with decreased survival in GBMs, did not have a distinct molecular signature. 30 This prior study assessed tumor mutations, DNA methylation, gene expression, and protein expression, which suggests that SVZ involvement and molecular alterations may be independent prognostic factors. Among LGGs, SVZ involvement by oligodendrogliomas was previously reported to be associated with a mutation in the Capicua transcriptional repressor gene.…”

Section: Discussionmentioning

confidence: 99%

The Prognostic Value of MRI Subventricular Zone Involvement and Tumor Genetics in Lower Grade Gliomas

Chiang

Pisapia

Liechty

et al. 2020

Journal of Neuroimaging

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BACKGROUND AND PURPOSE: Glioblastomas (GBMs) that involve the subventricular zone (SVZ) have a poor prognosis, possibly due to recruitment of neural stem cells. The purpose of this study was to evaluate whether SVZ involvement by lower grade gliomas (LGG), WHO grade II and III, similarly predicts poorer outcomes. We further assessed whether tumor genetics and cellularity are associated with SVZ involvement and outcomes. METHODS: Forty-five consecutive LGG patients with preoperative imaging and next generation sequencing were included in this study. Regional SVZ involvement and whole tumor apparent diffusion coefficient (ADC) values, as a measure of cellularity, were assessed on magnetic resonance imaging. Progression was determined by RANO criteria. Kaplan-Meier curves and Cox regression analyses were used to determine the hazard ratios (HR) for progression and survival. RESULTS: Frontal, parietal, temporal, and overall SVZ involvement and ADC values were not associated with progression or survival (P ≥ .05). However, occipital SVZ involvement, seen in two patients, was associated with a higher risk of tumor progression (HR = 6.6, P = .016) and death (HR = 31.5, P = .015), CDKN2A/B mutations (P = .03), and lower ADC histogram values at the 5th (P = .026) and 10th percentiles (P = .046). Isocitrate dehydrogenase, phosphatase and tensin homolog, epidermal growth factor receptor, and cyclin-dependent kinase 4 mutations were also prognostic (P ≤ .05). CONCLUSIONS: Unlike in GBM, overall SVZ involvement was not found to strongly predict poor prognosis in LGGs. However, occipital SVZ involvement, though uncommon, was prognostic and found to be associated with CDKN2A/B mutations and tumor hypercellularity. Further investigation into these molecular mechanisms underlying occipital SVZ involvement in larger cohorts is warranted.

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Section: Introductionmentioning

confidence: 99%

“…Glioblastomas with and without VSVZ invasion or contact are not genomically distinct in bulk profiling (9,10). Therefore, the more severe clinical phenotype of those patients is likely due t o t h e m i c r o e n v i r o n m e n t o f t h e V S V Z ( 9 ) . T h e microenvironment is especially attractive to glioblastoma cells (11,12), and factors released by the VSVZ can mediate resistance to radiation therapy in glioblastoma cells (13).…”

Section: Introductionmentioning

confidence: 99%

Glioblastoma Distance From the Subventricular Neural Stem Cell Niche Does Not Correlate With Survival

et al. 2020

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ObjectiveTo determine the relationship between survival and glioblastoma distance from the ventricular-subventricular neural stem cell niche (VSVZ).Methods502 pre-operative gadolinium-enhanced, T1-weighted MRIs with glioblastoma retrieved from an institutional dataset (n = 252) and The Cancer Imaging Atlas (n=250) were independently reviewed. The shortest distance from the tumor contrast enhancement to the nearest lateral ventricular wall, the location of the VSVZ, was measured (GBM-VSVZDist). The relationship of GBM-VSVZDist with the proportion of glioblastomas at each distance point and overall survival was explored with a Pearson’s correlation and Cox regression model, respectively, adjusting for the well-established glioblastoma prognosticators.Results244/502 glioblastomas had VSVZ contact. The proportion of non-VSVZ-contacting glioblastomas correlated inversely with GBM-VSVZDist (partial Pearson’s correlation adjusted for tumor volume R=-0.79, p=7.11x10-7). A fit of the Cox regression model adjusted for age at diagnosis, Karnofsky performance status score, post-operative treatment with temozolomide and/or radiotherapy, IDH1/2 mutation status, MGMT promoter methylation status, tumor volume, and extent of resection demonstrated a significantly decreased overall survival only when glioblastoma contacted the VSVZ. Overall survival did not correlate with GBM-VSVZDist.ConclusionsIn the two independent cohorts analyzed, glioblastomas at diagnosis were found in close proximity or in contact with the VSVZ with a proportion that decreased linearly with GBM-VSVZDist. Patient survival was only influenced by the presence or absence of a gadolinium-enhanced glioblastoma contact with the VSVZ. These results may guide analyses to test differential effectiveness of VSVZ radiation in VSVZ-contacting and non-contacting glioblastomas and/or inform patient selection criteria in clinical trials of glioblastoma radiation.

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Ventricular-Subventricular Zone Contact by Glioblastoma is Not Associated with Molecular Signatures in Bulk Tumor Data

Cited by 29 publications

References 51 publications

Adverse prognosis of glioblastoma contacting the subventricular zone: Biological correlates

Adverse prognosis of glioblastoma contacting the subventricular zone: Biological correlates

The Prognostic Value of MRI Subventricular Zone Involvement and Tumor Genetics in Lower Grade Gliomas

Glioblastoma Distance From the Subventricular Neural Stem Cell Niche Does Not Correlate With Survival

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