Blood-Based Biomarkers for Glioma in the Context of Gliomagenesis: A Systematic Review

Abstract

Background: Gliomas are the most common and aggressive tumors of the central nervous system. A robust and widely used blood-based biomarker for glioma has not yet been identified. In recent years, a plethora of new research on blood-based biomarkers for glial tumors has been published. In this review, we question which molecules, including proteins, nucleic acids, circulating cells, and metabolomics, are most promising blood-based biomarkers for glioma diagnosis, prognosis, monitoring and other purposes, and align them to the seminal processes of cancer.

Methods: The Pubmed and Embase databases were systematically searched. Biomarkers were categorized in the identified biomolecules and biosources. Biomarker characteristics were assessed using the area under the curve (AUC), accuracy, sensitivity and/or specificity values and the degree of statistical significance among the assessed clinical groups was reported.

Results: 7,919 references were identified: 3,596 in PubMed and 4,323 in Embase. Following screening of titles, abstracts and availability of full-text, 262 articles were included in the final systematic review. Panels of multiple biomarkers together consistently reached AUCs >0.8 and accuracies >80% for various purposes but especially for diagnostics. The accuracy of single biomarkers, consisting of only one measurement, was far more variable, but single microRNAs and proteins are generally more promising as compared to other biomarker types.

Conclusion: Panels of microRNAs and proteins are most promising biomarkers, while single biomarkers such as GFAP, IL-10 and individual miRNAs also hold promise. It is possible that panels are more accurate once these are involved in different, complementary cancer-related molecular pathways, because not all pathways may be dysregulated in cancer patients. As biomarkers seem to be increasingly dysregulated in patients with short survival, higher tumor grades and more pathological tumor types, it can be hypothesized that more pathways are dysregulated as the degree of malignancy of the glial tumor increases. Despite, none of the biomarkers found in the literature search seem to be currently ready for clinical implementation, and most of the studies report only preliminary application of the identified biomarkers. Hence, large-scale validation of currently identified and potential novel biomarkers to show clinical utility is warranted.

Keywords: blood; diagnostics; glioblastoma; glioma; liquid biopsy.

Figure 1

Timeline of clinical events for glioma patients and possible blood-based biomarkers that could be employed at different points in time. The straight lines indicate timelines for two example glioma patients [upper blue line for a lower-grade glioma (LGG) patient, lower red line for a high-grade glioma (HGG) patient]. Clinical events that occur on either timeline are indicated using dots and the clinical events are described in boxes connected to the dots. Early diagnostic markers have been found more than two decades before glioma diagnosis and could be used as a screening tool in the healthy population for patients older than 50 years. At the time of clinical or radiological findings that may indicate the growth of a glial tumor, diagnostic, tumor grade and disease differentiating biomarkers may be used to supplement the diagnostic procedure. Following, surgery (tumor tissue biopsy and/or tumor resection) may be performed, including either tumor resection or only a tumor tissue biopsy for definite histopathological diagnosis. At this point, the brain tumor is identified as a HGG or LGG. Following discussion of the case in a multidisciplinary tumor board, treatment may be initiated in patients with more malignant tumor types, while patients with less malignant tumor types may be subjected to frequent follow-up using monitoring markers and radiological imaging to monitor potential tumor progression. At the moment of tumor progression in patients with less malignant tumors or directly after surgical resection in patients with malignant tumors, predictive markers may provide additional information on the potential benefit of adjuvant treatment. Anti-tumor treatment with conventional chemo- and/or radiotherapy (CCR) is currently usually initiated at this point. Monitoring blood markers can detect tumor volume decrease over time. Patients with complete or partial response can be followed using radiological imaging and monitoring markers to distinguish between tumor progression or pseudoprogression. Patients with stable disease, progressive disease or tumor progression after complete or partial response may be admitted for experimental treatments. For each biomarker purpose, several potential blood-based biomarkers are listed ^aTocopherols; ^bmiR-21; ^cGFAP; ^dPanels of miRNAs, proteins and metabolites; ^eIL-10; ^fNLR; ^gYKL-40; ^hF-NLR; ⁱF-NLR-AGR. Figure was adapted from “Cell Transfer Protocol”, by BioRender.com (2021). Retrieved from: https://app.biorender.com/biorender-templates.

Figure 2

Overview of possible blood-based biomarkers for glioma and their purposes. Schematic overview of the several biosources (plasma, serum, extracellular vesicles, blood platelets, circulating immune cells, and circulating glioma tumor cells) and biomolecules (proteins, nucleic acids, metabolomics and peptides) that are identified for patients with glioma. These biomolecules can be collected in a vial of blood, and employed as a diagnostic, prognostic, predictive, or therapy monitoring marker. Figure was created with BioRender.com.

Figure 3

PRISMA diagram showing the amount of records found through database searching and reference checking, the amount of records screened and removed using exclusion criteria and the amount of records included in the final qualitative synthesis.

Figure 4

Correlation of blood-based biomarkers in patients with glioma with seminal events in tumorigenesis. Blood biomarkers in glioma patients are implicated in the molecular pathways as detailed by Hanahan and Weinberg (321). Markers colored in green were mostly found to be increased in the circulation of glioma patients compared to healthy individuals, and in glioma patients with more malignant tumors compared to patients with less malignant tumors. Markers that were inversely correlated were colored in red. Markers without color were found to be either significantly increased or decreased in the formerly mentioned groups. The abbreviation “DC” indicates dendritic cells and “iDC” indicates immature dendritic cells. Adapted from “Hallmarks of Cancer: Circle”, by BioRender.com (2021). Retrieved from: https://app.biorender.com/biorender-templates.