Abstract
Improving outcomes for diffuse glioma patients requires methods that can accurately and sensitively monitor tumour activity and treatment response. Extracellular vesicles (EV) are membranous nanoparticles that can traverse the blood–brain-barrier, carrying oncogenic molecules into the circulation. Measuring clinically relevant glioma biomarkers cargoed in circulating EVs could revolutionise how glioma patients are managed. Despite their suitability for biomarker discovery, the co-isolation of highly abundant complex blood proteins has hindered comprehensive proteomic studies of circulating-EVs. Plasma-EVs isolated from pre-operative glioma grade II–IV patients (n = 41) and controls (n = 11) were sequenced by Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) and data extraction was performed by aligning against a custom 8662-protein library. Overall, 4054 proteins were measured in plasma-EVs. Differentially expressed proteins and putative circulating-EV markers were identified (adj. p-value < 0.05), including those reported in previous in-vitro and ex-vivo glioma-EV studies. Principal component analysis showed that plasma-EV protein profiles clustered according to glioma histological-subtype and grade, and plasma-EVs resampled from patients with recurrent tumour progression grouped with more aggressive glioma samples. The extensive plasma-EV proteome profiles achieved here highlight the potential for SWATH-MS to define circulating-EV biomarkers for objective blood-based measurements of glioma activity that could serve as ideal surrogate endpoints to assess tumour progression and allow more dynamic, patient-centred treatment protocols.
Highlights
Diffuse gliomas are the most common and devastating primary malignant brain tumours of adults, owing to their characteristic diffusely invasive growth patterns
We previously showed that proteins cargoed in Extracellular vesicles (EV) surgically captured from tumour microenvironments can distinguish high-grade from low-grade glioma patients [28,29]
We previously reported significantly higher CCT2 and CCT7 levels in GBM neurosurgical aspirate-EVs compared to GII-III glioma, with analogous transcript expression levels and DNA copy numbers reported for CCT2 and CCT7 in GBM tissue compared to normal brain in TCGA datasets [28]
Summary
Diffuse gliomas are the most common and devastating primary malignant brain tumours of adults, owing to their characteristic diffusely invasive growth patterns. The most prominent distinguishing molecular feature of diffuse gliomas is the isocitrate dehydrogenase (IDH) mutational status which separates tumours into two broad categories. IDH-wildtype (IDH-wt) astrocytic tumours arise as primary de novo glioblastomas (GBM; astrocytoma grade IV) and are the most frequent and aggressive manifestations of diffuse glioma. GBM tumours often re-emerge as evolved, treatment-resistant entities and death typically ensues within 6-months of recurrence [2]. IDH mutations confer a prognostic advantage and are diagnostic of grade II–III gliomas or secondary GBMs that have progressed from grade II–III astrocytomas [5,6]. Tumours with IDH-mutations (IDH-mut) are further subdivided according to 1p/19q codeletion status, where oligodendrogliomas harbour both IDH-mut and 1p/19q codeletion and carry the most favourable prognosis. Malignant progression of IDH-mut gliomas is common, including the appearance of a ‘hypermutation phenotype’ following TMZ therapy [7]
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