Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Oct 11;14(10):e0222717.
doi: 10.1371/journal.pone.0222717. eCollection 2019.

Adverse prognosis of glioblastoma contacting the subventricular zone: Biological correlates

Sharon Berendsen  1 , Emma van Bodegraven  2 , Tatjana Seute  1 , Wim G M Spliet  3 , Marjolein Geurts  1 , Jeroen Hendrikse  4 , Laurent Schoysman  5   6 , Willemijn B Huiszoon  1 , Meri Varkila  1 , Soufyan Rouss  1 , Erica H Bell  7 , Jérôme Kroonen  1   5 , Arnab Chakravarti  7 , Vincent Bours  5 , Tom J Snijders  1 , Pierre A Robe  1   5   7
Affiliations

Adverse prognosis of glioblastoma contacting the subventricular zone: Biological correlates

Sharon Berendsen et al. PLoS One. .

Abstract

Introduction: The 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.

Methods: We 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.

Results: Involvement 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.

Conclusion: In 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.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Overview of study cohorts.
Abbreviations: UMCU: University Medical Center Utrecht; FFPE: Formalin fixed paraffin embedded; GBM: glioblastoma; EMT: epithelial-mesenchymal transition; TCGA: The Cancer Genome Atlas; TCIA: The Cancer Imaging Archive.
Fig 2
Fig 2. SVZ involvement associates with glioblastoma patient survival.
A. Pre-operative T1-weighted MRI scan with gadolinium of patient (M, 1928) with glioblastoma contacting the SVZ. B. Pre-operative T1-weighted MRI scan with gadolinium of patient (F, 1925) with glioblastoma not contacting the SVZ. C. Association of tumor contact with the SVZ on glioblastoma patient survival. Kaplan-Meier plot of glioblastoma patients with a tumor contacting the SVZ (grey) and patients with a tumor that does not contact the SVZ (black). Patients with survival over 1000 days from surgery were censored. Survival was significantly different between the two groups (log-rank test, P < 0.00005).
Fig 3
Fig 3. SVZ involvement in glioblastoma correlates with increased protein expression of key markers of (epithelial-)mesenchymal transformation.
Increased protein expression levels of (epithelial-)mesenchymal transformation markers C/EBP-β (Mann Whitney U test, P = 0.029) and PY705-STAT3 (Mann Whitney U test, P = 0.002), but not PS536-p65, were observed in glioblastomas contacting the SVZ. No expression differences in stem cell markers CD133 or GFAP-δ were observed between tumors with or without SVZ contact.
See this image and copyright information in PMC

References

    1. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015;314(23):2535–43. 10.1001/jama.2015.16669 - DOI - PubMed
    1. Ellingson BM, Cloughesy TF, Pope WB, Zaw TM, Phillips H, Lalezari S, et al. Anatomic localization of O6-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated tumors: a radiographic study in 358 de novo human glioblastomas. NeuroImage. 2012;59(2):908–16. 10.1016/j.neuroimage.2011.09.076 - DOI - PubMed
    1. Smith TR, Hulou MM, Abecassis J, Das S, Chandler JP. Use of preoperative FLAIR MRI and ependymal proximity of tumor enhancement as surrogate markers of brain tumor origin. Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia. 2015;22(9):1397–402. 10.1016/j.jocn.2015.02.029 - DOI - PubMed
    1. Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. The New England Journal of Medicine. 2005;353(8):811–22. 10.1056/NEJMra043666 - DOI - PubMed
    1. Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P, McKeever PE, et al. Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell. 2009;15(6):514–26. 10.1016/j.ccr.2009.04.001 - DOI - PMC - PubMed

Publication types

MeSH terms