Background: There is an unmet need for the identification of biomarkers to aid in the diagnosis, clinical management, prognosis and follow-up of meningiomas, facilitated by recent advances in meningioma genomics. WHO grade II meningiomas remain a controversial group of CNS tumours to diagnose/treat, compared to the more prevalent and extensively researched grade I tumours. Aim: To identify molecular signatures (biomarkers) unique to grade II meningiomas (versus grade I). Methods: I combined literature review with an unbiased global proteomic analysis of four grade I and four grade II primary (meningioma) cell cultures, to identify proteins differentially expressed between both grades. Validation of the significantly differentially expressed proteins was then performed by Western blotting (WB) and quantitative polymerase chain reaction (qPCR) in primary cells; via WB, immunohistochemistry and qPCR in tissue; and in plasma, via enzyme-linked immunosorbent assay (ELISA). Results: I identified 3554 proteins commonly expressed in both meningioma grades. Further analysis revealed that 86 of these were significantly-differentially up/down-regulated. Initial validation studies on some of the promising candidates have confirmed the patterns of expression between the two tumour grades. Of these 86, we discovered that the calcium binding extracellular matrix glycoprotein, Fibulin-2 was significantly differentially expressed between grade I and II meningiomas, at protein and gene expression levels. Proteomic analyses (p<0.05), Western blotting (p<0.01) and qPCR (p<0.01) confirmed significantly higher Fibulin-2 expression levels in grade II meningiomas compared to grade I. To distinguish between grade I and II meningiomas, Receiver Operating Characteristic (ROC) analysis of Fibulin-2 qPCR expression levels in meningioma tissue indicated an AUC of 0.73 (96% specificity). Fibulin-2 blood plasma levels were also significantly higher in grade II meningioma patients compared to grade I patients (cut-off value >2.5ng/ml with 95% specificity). Conclusion: The findings of this study have identified novel biomolecular differences between grade I/II meningiomas that can potentially aid in the diagnosis and clinical management of grade II meningiomas. Elevated Fibulin- 2 levels is proposed as a novel grade II meningioma biomarker, when differentiating them from the grade I tumours. The trend of Fibulin-2 expression observed in plasma may serve as a useful non-invasive biomarker.

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