Abstract
Glioblastoma (GB) remains an aggressive malignancy with an extremely poor prognosis. Discovering new candidate drug targets for GB remains an unmet medical need. Caveolin-1 (Cav-1) has been shown to act variously as both a tumour suppressor and tumour promoter in many cancers. The implications of Cav-1 expression in GB remains poorly understood. Using clinical and genomic databases we examined the relationship between tumour Cav-1 gene expression (including its spatial distribution) and clinical pathological parameters of the GB tumour and survival probability in a TCGA cohort (n=155) and CGGA cohort (n=220) of GB patients. High expression of Cav-1 represented a significant independent predictor of shortened survival (HR = 2.985, 5.1 vs 14.9 months) with a greater statistically significant impact in female patients and in the Proneural and Mesenchymal GB subtypes. High Cav-1 expression correlated with other factors associated with poor prognosis: IDH w/t status, high histological tumour grade and low KPS score. A total of 4879 differentially expressed genes (DEGs) in the GB tumour were found to correlate with Cav-1 expression (either positively or negatively). Pathway enrichment analysis highlighted an over-representation of these DEGs to certain biological pathways. Focusing on those that lie within a framework of epithelial to mesenchymal transition and tumour cell migration and invasion we identified 27 of these DEGs. We then examined the prognostic value of Cav-1 when used in combination with any of these 27 genes and identified a subset of combinations (with Cav-1) indicative of co-operative synergistic mechanisms of action. Overall, the work has confirmed Cav-1 can serve as an independent prognostic marker in GB, but also augment prognosis when used in combination with a panel of biomarkers or clinicopathologic parameters. Moreover, Cav-1 appears to be linked to many signalling entities within the GB tumour and as such this work begins to substantiate Cav-1 or its associated signalling partners as candidate target for GB new drug discovery.
Highlights
In adults, gliomas account for the majority of all primary malignant brain tumours, with over 50% of all gliomas constituted by the grade IV astrocytoma, glioblastoma multiforme (GB) [1]
We extended the analysis to the Chinese Glioma Genome Atlas (CGGA) database (n=220 patients) which yielded 6.12 as a value of mRNA that dichotomized the GB cohort in “high” and “low” expression of Cav-1 (Figure 1B)
In the the Cancer Genome Atlas (TCGA) database, patients with high expression of Cav-1 had a mean survival of 5.1 months compared with 14.9 months for patients with a low expression of the gene (Figure 2A)
Summary
Gliomas account for the majority of all primary malignant brain tumours, with over 50% of all gliomas constituted by the grade IV astrocytoma, glioblastoma multiforme (GB) [1]. GB is one of the most aggressive tumours in humans. By the time of diagnosis, its highly invasive character often limits success in the total surgical resection of the tumour. It is a tumour prone to recurrence, with 5-year survival rates of no more than 5% [2] and which have not notably improved over the last three decades [3]. Effective medical treatment for GB is a major unmet oncology need that will benefit from identification of robust predictive biomarkers that stratify patients at “high” or “low” risk of disease progression, and by the description of clinically meaningful molecular markers relevant for novel targeted therapies
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