Molecular prognostic factors in glioblastoma: state of the art and future challenges

Nandhabalan, Meera; Jones, Chris; Costa, Bruno M.

doi:10.2217/cns.13.48

Cited by 10 publications

(9 citation statements)

References 134 publications

(127 reference statements)

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“…There are several prognostic biomarkers identified in glioblastoma patients that may aid in stratifying subgroups of glioblastoma and rationalizing treatment decisions for individual patient. MGMT promoter methylation status and IDH1 mutations are two common biomarkers of prognosis in glioblastoma patients [5][6][7]. Our meta-analysis supports that high CD133 expression is associated with worse prognosis in patients with glioblastoma, and it may be another good biomarker for prognosis in glioblastoma patients.…”

Section: Discussionsupporting

confidence: 73%

“…To improve the prognosis of glioblastoma patients, identification of prognostic factors is helpful to individual treatment of glioblastoma [1,4]. There are several genetic biomarkers identified to be prognostic factors of glioblastoma, such as O(6)-methylguanine-methyltransferase (MGMT) promoter methylation status and isocitrate dehydrogenase 1 (IDH1) mutation [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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High CD133 Expression Is Associated with Worse Prognosis in Patients with Glioblastoma

Zhang

Chen

et al. 2015

Mol Neurobiol

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The CD133 antigen has been identified as a putative stem cell marker in gliomas. However, the prognostic significance of CD133 expression in glioblastoma patients remained controversial. A meta-analysis of published data was performed to comprehensively assess the prognostic role of CD133 expression in glioblastoma patients. Publications assessing the prognostic significance of CD133 expression in glioblastoma patients were identified in PubMed, Embase, and Web of Science up to November 2014. The pooled hazard ratio (HR) with 95% confidence interval (95% CI) was calculated using meta-analysis to evaluate the prognostic significance of CD133 expression in glioblastoma. Ten studies with a total of 715 glioblastoma patients were included into the meta-analysis. Overall, high CD133 expression was associated with poorer overall survival in patients with glioblastoma (HR = 1.96, 95% CI 1.46-2.64, P < 0.001). In addition, high CD133 expression was also associated with poorer progression-free survival in patients with glioblastoma (HR = 2.03, 95% CI 1.43-2.88, P < 0.001). Meta-analyses of studies with high quality showed that high CD133 expression was associated with both poorer overall survival (HR = 2.39, 95% CI 1.77-3.23, P < 0.001) and poorer progression-free survival (HR = 2.17, 95% CI 1.60-2.94, P < 0.001) in patients with glioblastoma. Meta-analysis of studies with adjusted estimates further showed that high CD133 expression was an independent prognostic factor of glioblastoma. High CD133 expression is associated with worse prognosis in patients with glioblastoma. More prospective studies with well-design are needed to confirm this finding.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

High CD133 Expression Is Associated with Worse Prognosis in Patients with Glioblastoma

Zhang

Chen

et al. 2015

Mol Neurobiol

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“…Understanding the biology of glioblastoma may lay the foundation for early diagnosis, prognosis, and treatment prediction, thus resulting in a better clinical outcome. With recent development of bioinformatics techniques and advances in omics such as genomics, transcriptomics, and proteomics, a variety of potential prognostic and predictive markers have been identified 29 . Among them, the methylation status of the MGMT gene promoter 30–33 and mutation in IDH1 and IDH2 genes 34–36 are the most promising prognostic biomarkers in GBM.…”

Section: Discussionmentioning

confidence: 99%

A robust two‐gene signature for glioblastoma survival prediction

Pan

Zhang

Guo

et al. 2020

J of Cellular Biochemistry

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Glioblastoma multiforme (GBM) is a highly malignant brain tumor. We explored the prognostic gene signature in 443 GBM samples by systematic bioinformatics analysis, using GSE16011 with microarray expression and corresponding clinical data from Gene Expression Omnibus as the training set. Meanwhile, patients from The Chinese Glioma Genome Atlas database (CGGA) were used as the test set and The Cancer Genome Atlas database (TCGA) as the validation set. Through Cox regression analysis, Kaplan-Meier analysis, t-distributed Stochastic Neighbor Embedding algorithm, clustering, and receiver operating characteristic analysis, a two-gene signature (GRIA2 and RYR3) associated with survival was selected in the GSE16011 dataset. The GRIA2-RYR3 signature divided patients into two risk groups with significantly different survival in the GSE16011 dataset (median: 0.72, 95% confidence interval [CI]: 0.64-0.98, vs median: 0.98, 95% CI: 0.65-1.61 years, logrank test P < .001), the CGGA dataset (median: 0.84, 95% CI: 0.70-1.18, vs median: 1.21, 95% CI: 0.95-2.94 years, logrank test P = .0017), and the TCGA dataset (median:1.03, 95% CI: 0.86-1.24, vs median: 1.23, 95% CI: 1.04-1.85 years, logrank test P = .0064), validating the predictive value of the signature. And the survival predictive potency of the signature was independent from clinicopathological prognostic features in multivariable Cox analysis. We found that after transfection of U87 cells with small interfering RNA, GRIA2 and RYR3 influenced the biological behaviors of proliferation, migration, and invasion of glioblastoma cells. In conclusion, the two-gene signature was a robust prognostic model to predict GBM survival. K E Y W O R D Sglioblastoma multiforme, prognostic, protein-coding genes, signature

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“…The effects observed in β-catenin in U373 and SNB19 cells clearly suggest that WNT6 might act through the canonical WNT pathway in GBM, which was further validated with the TCF/LEF reporter assays in U373 and U87 cells ( Figure S6 ). In addition, WNT6 silencing led to reduced phosphorylation/activation states of 4 non-receptor tyrosine Src kinases (Fgr, Yes, Fyn and Src), which have been described to contribute to the activation of downstream targets of RTKs, such as EGFR, influencing glioma aggressiveness 49 - 51 . WNT6 silencing also resulted in decreased phosphorylation of HSP27, an anti-apoptotic protein 52 associated with increased cell proliferation and decreased Fas-induced apoptosis in prostate cancer 53 , and was shown to mediate the activation of p38/ERK (MAPK) pro-survival signaling in cervical cancer cells 54 .…”

Section: Discussionmentioning

confidence: 99%

WNT6 is a novel oncogenic prognostic biomarker in human glioblastoma

Gonçalves¹,

Castro²,

Pojo³

et al. 2018

Theranostics

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Glioblastoma (GBM) is a universally fatal brain cancer, for which novel therapies targeting specific underlying oncogenic events are urgently needed. While the WNT pathway has been shown to be frequently activated in GBM, constituting a potential therapeutic target, the relevance of WNT6, an activator of this pathway, remains unknown.Methods: WNT6 protein and mRNA levels were evaluated in GBM. WNT6 levels were silenced or overexpressed in GBM cells to assess functional effects in vitro and in vivo. Phospho-kinase arrays and TCF/LEF reporter assays were used to identify WNT6-signaling pathways, and significant associations with stem cell features and cancer-related pathways were validated in patients. Survival analyses were performed with Cox regression and Log-rank tests. Meta-analyses were used to calculate the estimated pooled effect.Results: We show that WNT6 is significantly overexpressed in GBMs, as compared to lower-grade gliomas and normal brain, at mRNA and protein levels. Functionally, WNT6 increases typical oncogenic activities in GBM cells, including viability, proliferation, glioma stem cell capacity, invasion, migration, and resistance to temozolomide chemotherapy. Concordantly, in in vivo orthotopic GBM mice models, using both overexpressing and silencing models, WNT6 expression was associated with shorter overall survival, and increased features of tumor aggressiveness. Mechanistically, WNT6 contributes to activate typical oncogenic pathways, including Src and STAT, which intertwined with the WNT pathway may be critical effectors of WNT6-associated aggressiveness in GBM. Clinically, we establish WNT6 as an independent prognostic biomarker of shorter survival in GBM patients from several independent cohorts.Conclusion: Our findings establish WNT6 as a novel oncogene in GBM, opening opportunities to develop more rational therapies to treat this highly aggressive tumor.

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Molecular prognostic factors in glioblastoma: state of the art and future challenges

Cited by 10 publications

References 134 publications

High CD133 Expression Is Associated with Worse Prognosis in Patients with Glioblastoma

High CD133 Expression Is Associated with Worse Prognosis in Patients with Glioblastoma

A robust two‐gene signature for glioblastoma survival prediction

WNT6 is a novel oncogenic prognostic biomarker in human glioblastoma

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