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  Table of Contents    
Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 111-121
Liquid biopsy in CNS tumors: Current status & future perspectives

Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

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Date of Submission28-Oct-2021
Date of Decision07-Dec-2021
Date of Acceptance22-Dec-2021
Date of Web Publication11-May-2022


Precise classification of central nervous system (CNS) malignancies is vital for the treatment and prognostication. Identification of noninvasive markers can be of importance to guide treatment decisions and in monitoring treatment response. CNS tumors are classified based on morphology with an essential complement of molecular changes, including mutations, amplifications, and methylation. Neuroimaging is the mainstay for initial diagnosis and monitoring tumor response with obvious limitations of imprecise tumor typing and no information on diagnostic, predictive and prognostic markers. Liquid biopsy has evolved as a diagnostic tool in body fluids and is being investigated as a surrogate for tissue biopsy in managing primary and metastatic brain tumors. Liquid biopsy refers to analyzing biological fluids such as peripheral blood, urine, pleural effusion, ascites, and cerebrospinal fluid (CSF); however, peripheral blood remains the primary source of fluid biopsy. The analytes include cell-free DNA (cfDNA) circulating tumor cells (CTCs), circulating micro RNAs (miRNAs), circulating proteins and extracellular vesicles (EVs). Analysis of these components is actively used for early cancer detection, auxiliary staging, prognosis assessment, detection of minimal residual disease (MRD), and monitoring drug resistance in various solid tumors. In recent years, liquid biopsy has been studied in CNS tumors, and analysis of CTCs and cfDNA have become relevant research topics. In the current review, we have explained the clinical potential of liquid biopsy in CNS tumors to assist in diagnosing and predicting prognosis and response to treatment.

Keywords: cfDNA, circulating miRNA, CNS tumors, CSF, CTCs, ctDNA, liquid biopsy, plasma

How to cite this article:
Husain N, Husain A, Mishra S, Srivastava P. Liquid biopsy in CNS tumors: Current status & future perspectives. Indian J Pathol Microbiol 2022;65, Suppl S1:111-21

How to cite this URL:
Husain N, Husain A, Mishra S, Srivastava P. Liquid biopsy in CNS tumors: Current status & future perspectives. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 24];65, Suppl S1:111-21. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/111/345034

   Introduction Top

The malignancies of the central nervous system (CNS) are among the most aggressive types of human tumors. They account for around 1.35 percent of all malignant neoplasms and 2.95 percent of cancer-related fatalities.[1] The pathophysiology of CNS malignancies remains a mystery. Genetic predisposition is critical. CNS tumors are a heterogeneous category of neoplasms, including primary brain tumors and metastatic disease. Glioblastoma are the most prevalent malignant CNS tumors arising from glial cells. Glioblastoma are particularly aggressive cranial tumors with a 5-year survival rate of less than 5%.[2] Magnetic resonance imaging (MRI) is currently the primary diagnostic method in individuals suspected of having a brain tumor. Examination of tumor tissue obtained via biopsy or excision and its specific genetic profiling is essential for identifying tumor type and grade of malignancy.[3]

Unfortunately, once a tumor is discovered under the microscope, it is frequently too late to control it effectively. A liquid biopsy that uses cfDNA, CTCs, miRNAs, exosomes, and other biomarkers detection may carry a potential for early detection. Minimally invasive diagnostic approaches are advantageous in a clinical setting where limitations to surgery exist. Further repeat biopsies are not possible, and liquid biopsy also finds use in following up the evolution of the tumor over time and with treatment.[4] We discuss the current and potential roles of liquid biopsy in treating CNS malignancies in this review.

   Liquid Biopsy Vs. Tissue Biopsy Top

Intracranial tumors are definitively diagnosed using tissue specimens collected after surgery. Invasive neurosurgery is required in current practice for retrieving tissue for diagnosis and molecular subtyping, which involves risks, neurological morbidity and concern for the patient. Noninvasive diagnostic procedures allow patients to avoid unnecessary surgery and risk. Reliable noninvasive solutions for diagnosing and subtyping tumors would dramatically affect patient care, either by improving neurosurgical planning or in the case of availability of other thereapeutic options, removing the need for very invasive treatments. Sampling circulating tumor DNA (ctDNA) from patients' body fluids, such as blood and CSF enables establishing a definite diagnosis noninvasively (i.e., liquid biopsy).[5],[6]

The tumor-tissue analysis is the gold standard for diagnosing and managing CNS tumors at the moment. Occasionally, surgery cannot be performed due to patient or tumor variables. Diagnosis of recurrence uses MRI as a mainstay which has limitations of distinguishing postradiation necrosis and gliosis from tumor recurrence in some cases following radiotherapy/chemoradiotherapy treatment. Liquid biopsy is a noninvasive method for real-time sampling of tumor cells or nucleotides from biofluids. It is a potential noninvasive method for monitoring CNS malignancies.[7] The ability to obtain tumor genetics and monitor tumor evolution in patients with CNS malignancies can transform clinical care for patients with CNS cancers in the same way that precision medicine has resulted in improvements in outcomes for systemic malignancies such as lung cancer.[8],[9],[10] Liquid biopsy approach in CNS tumors with blood and CSF modalities are depicted in [Figure 1].
Figure 1: Liquid biopsy of blood and CSF in central nervous system tumors

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   Cell-Free DNA (CfDNA) Top

CfDNA is a naturally occurring component of blood at low quantities (1–10 ng/mL), and its levels are elevated during various physiological and pathological activities, including exercise, infection, trauma, and cancer.[11] Blood cfDNA is derived primarily from genomic DNA released during inflammation or cell death in patients without cancer. The content of cfDNA in the blood is low under healthy conditions due to its clearance by phagocytes.[12] Cancer derived cfDNA is referred to as ctDNA.[13] They are believed to be released after tumor tissue disintegration via tumor cell death_and/or necrosis or direct secretion of EVs into the circulation.[14] Increased levels of cfDNA are detected in the blood of patients with advanced solid tumors, and this has been extensively investigated.[15],[16],[17],[18]

There are two basic approaches for detecting ctDNA: specialized assays for specific mutations and broad sequencing panels as depicted in [Figure 2]. The total amount of ctDNA in the blood range from less than 0.1% to 5% of total cfDNA, depending on the tumor type, grade, and burden.[15],[19] The leaky blood-brain barrier in tumors and shedding of ctDNA into the cerebrospinal fluid (CSF) make both plasma or serum and CSF potential samples for liquid biopsy.
Figure 2: cfDNA mutational analysis with targetable and broad approaches

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Adult diffuse glioma

Studies have demonstrated the presence of ctDNA in primary CNS malignancies, including astrocytoma and oligoastrocytoma.[20],[21],[22] Glioblastoma has a high concentration and positive ctDNA index in serum.[23] In early reports, ctDNA was detected in less than 10% of gliomas, a rate substantially lower than other malignancies.[24] However, as sequencing depth and polymerase chain reaction (PCR) techniques improved, other authors have reported increased detection. A quantification study by Bagley et al.[24] reported considerably higher levels of cfDNA in patients with Glioblastoma than healthy controls, whereas Boisselier et al.[25] reported that larger or enhancing tumors had higher levels of the isocitrate dehydrogenase 1 (IDH1)-R132H mutation. Lavon et al.[26] detected ctDNA in the plasma of 53% of 70 gliomas using a combination of genetic and/or epigenetic changes with detection rate in oligodendroglioma (100%) and astrocytoma (80.5%) patients. methylguanine DNA methyltransferase (MGMT) gene methylated/10q LOH/1p or 19q LOH were also detected in ctDNA. In serum sample of 33 CNS tumors, including 07 primary Glioblastoma, 08 astrocytomas, 02 gliomas, 06 meningiomas, and 10 metastatic tumors, RASSF2B, CDKN2A gene were found methylated for at least 1 gene in 70% astrocytoma group.[27] Muralidharan et al.[28] analyzed 157 adult gliomas for telomerase reverse transcriptase gene (TERT) promoter mutation with sensitivity and specificity of 62.5% and 90.0%, respectively. Increased mutant allele frequency was found in a patient with recurrence, suggesting TERT mutation's role as a marker for disease progression. In a case-control study, Li et al.[29] using 38 gliomas and 42 nonglioma control samples, developed an epigenetic liquid biopsy score with sensitivity and specificity of 100% and 97.8%, respectively for discrimination between glioma and nonglioma patients. This scoring system showed potential in monitoring the disease progression and treatment response.[30] Multigene sequencing platforms have been able to successfully detect mutations in ctDNA in 50%–55% of Glioblastoma patients.[17],[21] Additional strategies for enhancing ctDNA detection include separating mitochondrial ctDNA,[31] assessing epigenetic modifications,[32] and targeting cfDNA with a specific fragment size to reduce background interference.[33] Plasma methylomes can accurately distinguish gliomas from controls and patients with intracranial metastasis and differentiate histological types of primary brain tumors, using only small amounts of cfDNA (1–10 ng) [Table 1].[34]
Table 1: ctDNA mutations in liquid biopsies of CNS tumor

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CSF is an attractive biofluid for ctDNA due to the low nontumor background of cfDNA and the anatomic closeness.[40],[46] Wang et al.[46] detected ctDNA in 74% of patients' CSF collected at the time of surgery, which increased to 100% when the tumor abutted a CSF space. Mouliere et al.[33] used shallow whole-genome sequencing (WGS) to detect single-copy number alterations in the CSF of glioma patients, implying that the concentration of ctDNA is significantly higher in CSF. Increased ctDNA levels occur in progressive disease, which spreads into CSF spaces with a significant tumor burden. A high degree of concordance between tumor tissue and CSF ctDNA mutations occurs, providing critical genetic information about a tumor.[33],[34],[40],[46],[52]

Comparing matched tumor tissue and ctDNA has also demonstrated a high degree of concordance in mutational profile, even detecting cancer-specific mutations in the blood missed during tissue biopsy.[53],[54],[55] It is hypothesized that ctDNA represents cells across a tumor, avoiding the intratumoral heterogeneity seen with tissue biopsy. However, the ways by which ctDNA is released remain unknown, including whether specific tumor cell subpopulations are mainly responsible.[55],[56],[57] A significant restriction in gliomas is the low amounts of ctDNA in the plasma, necessitating extremely sensitive detection methods. Although CSF looks to be a superior option over peripheral blood, its frequent usage in neurooncology clinics is limited. Although clinical application of liquid biopsies using cfDNA has been implemented for some malignancies like lung tumors, they have not been validated in glioma or other CNS malignancies.

In our preliminary study of gliomas, preoperative cfDNA level was significantly higher in cases (712.42 ± 606.52 ng/mL) as compared to healthy controls (88.93 ± 50.38 ng/mL) (P = 0.001). Increased cfDNA levels were significantly associated with the grade of disease (P = 0.0001), age >45 years, and TP53 mutation. The area under the curve in Receiver Operator Curves (ROC) curve for glioma versus normal controls was with sensitivity, specificity, and diagnostic accuracy of 79.8%, 100.0%, and 82.0%, respectively.[58] In serial follow-up samples, pre-radiotherapy cfDNA levels were higher in patients with adult diffuse glioma (ADG) (Median; 103.0 ng/mL) as compared to normal controls (Median; 74.37 ng/mL) (P = 0.04). Serial quantification showed a decreasing trend with mean (Q1-Q3) values of 103.0 (26.23–279.20), 88.27 (23.25–156.70), and 75.05 (28.26–208.20) (P = 0.04) in preradiotherapy, 3-week, and 6-week samples, respectively. The mutation was detected in 85.71% of cases in pre-operative cfDNA samples using a glioma tailored panel (TP53, IDH1/2, ATRX). Mutations were also detected in all postoperative cfDNA with at least one mutation. For TP53 gene mutation, the concordance rate was 100%.

Pediatric gliomas

CfDNA has also been studied in pediatric gliomas. Izquierdo et al.[59] reported higher cfDNA concentration in plasma from radiated pediatric diffuse midline glioma patients. Although the yield of cfDNA in non-CNS tumor plasma is only marginally higher (6.0 vs. 5.3 ng of cfDNA per mL of plasma) because 99% of cfDNA is nontumor DNA, significant differences in the abundance of the remaining 1% of cfDNA in CNS vs. non-CNS tumors are not apparent when comparing total cfDNA values.[60] In the context of tumor mutation testing, the accuracy of BRAF V600E mutant identification using droplet digital PCR in plasma cfDNA of 29 pediatric patients with medulloblastomas, ependymomas, or gliomas was low (sensitivity 25%, specificity 78%).[47]

The most successful application of CSF cfDNA is the identification of brain stem tumors, which are notoriously difficult and dangerous to biopsy. In brain stem malignancies, tumor-specific mutations have been discovered in the CSF cfDNA of 82.5% of patients using next-generation sequencing (NGS) of 68 genes panel with a sensitivity of 75%.[41] Histone 3 allele-specific PCR and single-gene Sanger sequencing tests have been designed to aid in the diagnosis of H3K27M-mutant diffuse midline gliomas, with 87.5% clinical sensitivity for CSF cfDNA when compared to tissue testing.[45],[61]

Epigenetic alterations have also been studied in ctDNA. Li et al.[29] identified 6,598 differentially methylated CpGs in pediatric medulloblastoma (MB) tumors in the CSF ctDNA compared with normal cerebellum, which could be used to detect MB tumor occurrence and determine its subtype. DNA methylation and hydroxymethylation signatures in CSF ctDNA can serve as valuable epigenetic markers to guide the clinical management of patients with MB. The epigenetic alterations detected in ctDNA can be exploited for their diagnostic potential.

CNS lymphoma

In contrast to solid primary CNS tumors, primary CNS lymphoma (PCNSL) is a differential diagnosis for space-occupying brain lesions,[62] and surgical management is not regularly part of treatment.[63] MYD88 L265P mutations in plasma cfDNA were discovered by digital droplet PCR in plasma cfDNA in 57% (8/14) patients with PCNSL.[49] Similarly, Fontanilles et al.[64] found plasma cfDNA mutations in only 32% of patients, including MYD88 mutations in 8 of 20 instances, using a focused NGS panel.

In patients with suspected PCNSL, CSF cytology and immunophenotyping by flow cytometry are currently employed as alternatives to stereotactic biopsy. CSF-derived cfDNA has a higher clinical sensitivity (86%) than plasma-derived cfDNA, and MYD88 L265P mutations can be found even in the absence of positive cytology or flow cytometry.[65] MYD88 L265P mutations are only found in primary CNS lymphoma (PCNSL) and have not been found in other brain cancers like Glioblastoma,[62],[63] making this a particularly interesting biomarker. In the future, it may be possible to diagnose PCNSL based on an MYD88 L265P molecular result alone, even if the cytology is negative.

   Circulating Tumor Cells Top

Collecting blood samples to analyze CTCs without surgical intervention is a more attractive alternative and have been reported in various epithelial cancers, including head and neck,[66] breast,[67] lung,[68] colorectal, gastric, pancreatic,[69] renal cell, urinary bladder, and prostate cancers,[70] gallbladder[71] and more recently in CNS malignancies.[72] CTCs detection in CNS tumors is vital because of the possible follow-up of disease status via a simple blood test that eliminates the surgical procedure that risks the patient's morbidity. The role of CTCs in brain tumors is still not well-defined. Clinically, the occurrence of CTCs is suggestive of a negative prognostic impact and highlights a role for these cells as biomarkers of disease progression and treatment response.

In CNS tumors, the CTCs have been detected in a range of 20% to 70%. The variation in detection rates may be attributed to heterogeneous identification methods, lack of standardized tumor-specific markers, and lack of uniform procedure. Using the Ficoll-based density gradient centrifugation followed by fluorescence immunocytochemistry, Müller et al.[73] identified the CTCs using glial fibrillary acidic protein (GFAP) marker in 20% of Glioblastoma patients and confirmed that Glioblastoma CTCs have a low proneural signature with a high epidermal growth factor receptor (EGFR) copy number. Due to significant differences in the size of CTCs compared to the other circulating cells, multiple microfluidic devices are commercially available to identify the CTCs although the low specificity hampers them.[74] A study by Sullivan et al.[75] used a similar micro-fluidic system using three antibodies- anti CD14, anti CD16, and anti CD45 to capture CTCs in 13/39 (33.33%) patients. Gao et al.[76] used integrated cellular and molecular approach of subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) and found the CTCs in the peripheral blood of 24/31 patients (77%) in all subtypes of gliomas, including Glioblastoma. Bang-Christensen et al.[77] identified CTCs in peripheral blood of glioma patients using recombinant malaria VAR2CSA protein (rVAR2) in gliomas. The characterization of CTCs in various gliomas subtypes suggests that the process of forming CTCs in the bloodstream across the BBB is not only identified in aggressive gliomas but also identified in benign primary CNS tumors. The Parsortix microfluidic technology in 13 Glioblastoma patients found clusters of CTCs ranging from 2 to 23 cells expressing EGFR, Ki67, and EB1 markers but negative for CD45. CTCs detection has been observed with recurrence of Glioblastoma and as well as in lower-grade gliomas due to the capability of CTCs to return to the tumor site via a reseeding mechanism to repopulate the brain.[78]

CTCs in CSF have been found with evidence of leptomeningeal disease with specificity and sensitivity of 100% and 92.7%, respectively, far more than any other prevailing modalities.[79] CTCs can be used to diagnose and metastatic epithelial tumors in CSF with high sensitivity and specificity of 93.0% and 95.0%, respectively.[80]

CSF is a more reliable source for CTCs identification than blood. CTCs can also be identified from the blood and CSF samples in pediatric brain tumor patients.[81] It has been found that CSF CTCs are more diagnostically efficient than peripheral blood in pediatric astrocytoma, ependymoma, and medulloblastoma.[82],[83] Antibody against glial fibrillary acidic protein (GFAP) bound to liposome beads has been used by Zhao et al.[84] to isolate CTCs in both the CSF and peripheral blood samples.

In CTCs, specific genotyping of primary tumors correlates with genetic alterations in recurrence. Mutational landscape in CTCs may help to screen the patient with a higher risk of recurrence and monitor the disease progression and treatment interventions [Table 2].
Table 2: Circulating Tumor Cells (CTCs) Studies in CNS Tumor

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   Circulating microRNA Top

miRNAs are short, single-stranded noncoding RNAs that account for approximately 1% of the human genome and regulate the translation and stability of 50% to 60% of mRNA by degradation and translational repression of mRNAs.[88] Over 2000 miRNAs have been identified, and evidence suggests that they play crucial biological roles in tumor growth, angiogenesis, and immune evasion.[88],[89] MiRNAs can cross through the blood-brain barrier and are stable in the blood either within exosomes or free circulation. Various up-regulated/down-regulated miRNAs have been utilized in the diagnosis and prognosis of gliomas [Table 3]. Diagnostic sensitivity of miRNAs in gliomas ranges from 58.5% to 99.05%, with specificity ranging from 66.7% to 100%. Up-regulation of miR-21 and down-regulation of MiR-128 and MiR-342-3p has been reported in Glioblastoma patients[90] MiR-21 was the most reliable and reproducible diagnostic biomarker of Glioblastoma in a meta-analysis by Qu et al.[91] A recent meta-analysis demonstrated that serum miRNA could differentiate between glioma patients and healthy controls with an area under the curve (AUC) of 0.93.[92] Serum miRNA levels correlate with tumor volume during the postoperative monitoring period but do not increase during pseudoprogression.[93]
Table 3: miRNA studies in gliomas

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Quantification of miRNA expression along with the data normalization to correct for variability during sample preparation is another major issue. The use of ddPCR has recently been shown to diminish the analytic variation with improved reproducibility. Clusters of upregulated and downregulated miRNA continue to be promising candidate biomarkers for the diagnosis of gliomas.

   Extracellular Vesicles Top

EVs have been implicated as mediators of repair and homeostasis in the central nervous system, whereas they may act as regulators of cell proliferation, clonogenicity, angiogenesis, thrombosis, and reciprocal tumor-stromal interactions in cancer. EVs produced by certain type of brain tumors cells may contain oncogenic drivers, such as epidermal growth factor receptor variant III (EGFRvIII) in Glioblastoma (and are hence frequently referred to as “oncosomes”). EVs enable the horizontal transfer of mutant oncoproteins and nucleic acids between cellular populations, modifying their individual and collective phenotypes. Oncogenic pathways also affect EVs' emission rates, kinds, cargo, and biogenesis as evidenced by preliminary investigations revealing differences in the profiles of EV-regulating genes (vesiculome) between Glioblastoma molecular subtypes and other brain cancers. Vesiculation-related molecular regulators can also function as oncogenes.

In gliomas, EVs interact with endothelial cells to promote angiogenesis and stimulate tumor cell growth in an autocrine manner. Skog et al.[113] isolated the EV from serum samples of brain tumors and detected genetic changes in the EGFR gene of these patients. Figueroa et al.[114] also detected EGFRvIII mutation in EVs of 60.86% of Glioblastoma patients. Noerholm et al.[115] detected different RNA expression patterns in serum samples of gliomas patients. High EVs concentration in plasma samples has been shown to associate with tumor recurrence after resection.[116] In temozolomide-treated Glioblastoma patients, the exosomal mRNA level of methylguanine DNA methyltransferase (MGMT) and alkylpurine-DNA-N glycosylase (APNG) correlate with the primary tumor and its level changes during the treatment.[102] A study by Chen et al.[117] used a CSF sample for EV mRNA analysis in glioma patients using the digital PCR and identified the mutant IDH1 mRNA in EVs in 5/8 patients; however, this could not be detected in matched serum-derived EVs.

EVs offer a minimally invasive diagnostic method as well as monitor treatment response in CNS tumors as these are packed with nucleic acids and proteins for further analysis. The heterogeneity and nonspecificity of the exosome content, when correlated to the tumor, is a limitation in diagnosis.[118] Enrichment strategies for glioma-derived exosomes are still being investigated,[119] and there is no standard method for distinguishing tumor and nontumor exosomes despite single-cell EV analysis[120] or widespread proteomic genetic profiling.[121]

   Proteomes and Metabolomes Top

Specific serum-derived proteins for glioma classification have been analyzed, and 27 differentially expressed proteins identified, of which few are associated with tumor progression.[122] The serum protein level of haptoglobin-2 is significantly associated with high-grade gliomas.[123] The expression level of YKL-40 in biopsy and serum samples is associated with overall survival and a worse prognosis of Glioblastoma patients.[124],[125] In Glioblastoma, the serum Alpha 2-HS Glycoprotein (AHSG) level is associated with a higher tumor grade and poor overall survival.[126] Controversies exist in these associations, and others have not observed haptoglobin-2, YKL-40, or AHSG associated with progression-free survival.[127]

Metabolites play a vital role in sustaining cancer cell proliferation and help to adapt to the microenvironment. Few studies in Glioblastoma support using metabolites as a specific biomarker in Glioblastoma liquid biopsy, including D2-hydroxyglutarate (2HG), a well-known oncometabolite, which accumulates in glioma cells with an IDH1 mutation.[128] Shen et al.[32] used metabolomic profiling in plasma of Glioblastoma patients and identified arginine, methionine, and kynurenate. Björkblom et al.[129] identified the higher serum concentration of tocopherol in Glioblastoma.

   Conclusions and Future Perspectives Top

The molecular analyses of ctDNA, circulating tumor cells, nucleic acids, proteins and metabolites, and exosomes have demonstrated promise for noninvasive CNS tumor identification and surveillance. Currently, most of these techniques are being explored independently and have not been integrated into the standard of care in neuro-oncology practice. The current phase of optimization of liquid biopsy approaches focuses on increasing the sensitivity of the methods used to detect tumor analytes in blood and CSF and expanding the number of molecular and histological subtypes that can be detected to aid in future clinical decision-making. After optimizing the testing platforms, it will be critical to test these procedures in prospective cohorts to prove their utility. Sensitivity and specificity of detecting CNS tumors in liquid biopsies for diagnosis and monitoring may be reached by utilizing multiple platforms like combining ctDNA and miRNA profiling. Liquid biopsy concerning CNS tumors may find application in early diagnosis, solving diagnostic dilemmas of tumor vs. nontumor in radiology, specific diagnosis, and mutation profiling when tissue is limited or the tumor is not surgically amenable, as well as for treatment follow up to determine for response to therapy as well as diagnosis of recurrence.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro-Oncology 2019;21:v1-100.  Back to cited text no. 1
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7-34.  Back to cited text no. 2
Stupp R, Brada M, van den Bent MJ, Tonn J-C, Pentheroudakis G. High-grade glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25:iii93-101.  Back to cited text no. 3
Boire A, Brandsma D, Brastianos PK, Le Rhun E, Ahluwalia M, Junck L, et al. Liquid biopsy in central nervous system metastases: A RANO review and proposals for clinical applications. Neuro Oncol 2019;21:571-84.  Back to cited text no. 4
De Mattos-Arruda L, Mayor R, Ng CKY, Weigelt B, Martínez-Ricarte F, Torrejon D, et al. Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun 2015;6:8839. doi: 10.1038/ncomms9839.  Back to cited text no. 5
Heitzer E, Haque IS, Roberts CES, Speicher MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet 2019;20:71-88.  Back to cited text no. 6
Marrugo-Ramírez J, Mir M, Samitier J. Blood-based cancer biomarkers in liquid biopsy: A promising non-invasive alternative to tissue biopsy. Int J Mol Sci 2018;19:2877.  Back to cited text no. 7
Fittall MW, Van Loo P. Translating insights into tumor evolution to clinical practice: Promises and challenges. Genome Med 2019;11:20.  Back to cited text no. 8
McEwen AE, Leary SES, Lockwood CM. Beyond the blood: CSF-derived cfDNA for diagnosis and characterization of CNS tumors. Front Cell Dev Biol 2020;8:45.  Back to cited text no. 9
Torres S, González Á, Cunquero Tomas AJ, Calabuig Fariñas S, Ferrero M, Mirda D, et al. A profile on cobas® EGFR mutation test v2 as companion diagnostic for first-line treatment of patients with non-small cell lung cancer. Expert Rev Mol Diagn 2020;20:575-82.  Back to cited text no. 10
El Messaoudi S, Rolet F, Mouliere F, Thierry AR. Circulating cell free DNA: Preanalytical considerations. Clin Chim Acta 2013;424:222-30.  Back to cited text no. 11
Kustanovich A, Schwartz R, Peretz T, Grinshpun A. Life and death of circulating cell-free DNA. Cancer Biol Ther 2019;20:1057-67.  Back to cited text no. 12
Sorenson GD, Pribish DM, Valone FH, Memoli VA, Bzik DJ, Yao SL. Soluble normal and mutated DNA sequences from single-copy genes in human blood. Cancer Epidemiol Biomarkers Prev 1994;3:67-71.  Back to cited text no. 13
Schwarzenbach H, Hoon DSB, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 2011;11:426-37.  Back to cited text no. 14
Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014;6:224ra24.  Back to cited text no. 15
Faria G, Silva E, Da Fonseca C, Quirico-Santos T. Circulating cell-free DNA as a prognostic and molecular marker for patients with brain tumors under perillyl alcohol-based therapy. Int J Mol Sci 2018;19:1610.  Back to cited text no. 16
Kumari S, Husain N, Agarwal A, Neyaz A, Gupta S, Chaturvedi A, et al. Diagnostic value of circulating free DNA integrity and global methylation status in gall bladder carcinoma. Pathol Oncol Res 2019;25:925-36.  Back to cited text no. 17
Kumari S, Tewari S, Husain N, Agarwal A, Pandey A, Singhal A, et al. Quantification of circulating free DNA as a diagnostic marker in gall bladder cancer. Pathol Oncol Res 2017;23:91-7.  Back to cited text no. 18
Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer 2017;17:223-38.  Back to cited text no. 19
Müller Bark J, Kulasinghe A, Chua B, Day BW, Punyadeera, C. Circulating biomarkers in patients with glioblastoma. Br J Cancer 2020;122:295-305.  Back to cited text no. 20
Piccioni DE, Achrol AS, Kiedrowski LA, Banks KC, Boucher N, Barkhoudarian G, et al. Analysis of cell-free circulating tumor DNA in 419 patients with glioblastoma and other primary brain tumors. CNS Oncol 2019;8:CNS34.  Back to cited text no. 21
Nørøxe DS, Østrup O, Yde CW, Ahlborn LB, Nielsen FC, Michaelsen SR, et al. Cell-free DNA in newly diagnosed patients with glioblastoma – a clinical prospective feasibility study. Oncotarget 2019;10:4397-406.  Back to cited text no. 22
Aili Y, Maimaitiming N, Mahemuti Y, Qin H, Wang Y. Liquid biopsy in central nervous system tumors: The potential roles of circulating miRNA and exosomes. Am J Cancer Res 2020;10:4134-50.  Back to cited text no. 23
Bagley SJ, Nabavizadeh SA, Mays JJ, Till JE, Ware JB, Levy S, et al. Clinical utility of plasma cell-free DNA in adult patients with newly diagnosed glioblastoma: A pilot prospective study. Clin Cancer Res 2020;26:397-407.  Back to cited text no. 24
Boisselier B, Gállego Pérez-Larraya J, Rossetto M, Labussière M, Ciccarino P, Marie Y, et al. Detection of IDH1 mutation in the plasma of patients with glioma. Neurology 2012;79:1693-8.  Back to cited text no. 25
Lavon I, Refael M, Zelikovitch B, Shalom E, Siegal T. Serum DNA can define tumor-specific genetic and epigenetic markers in gliomas of various grades. Neuro Oncol 2010;12:173-80.  Back to cited text no. 26
Majchrzak-Celińska A, Paluszczak J, Kleszcz R, Magiera M, Barciszewska AM, Nowak S. Detection of MGMT, RASSF1A, p15INK4B, and p14ARF promoter methylation in circulating tumor-derived DNA of central nervous system cancer patients. J Appl Genetics 2013;54:335-44.  Back to cited text no. 27
Muralidharan K, Yekula A, Small JL, Rosh ZS, Kang KM, Wang L, et al. TERT promoter mutation analysis for blood-based diagnosis and monitoring of gliomas. Clin Cancer Res 2021;27;169-78.  Back to cited text no. 28
Li J, Zhao S, Lee M, Yin Y, Li J, Zhou Y, et al. Reliable tumor detection by whole-genome methylation sequencing of cell-free DNA in cerebrospinal fluid of pediatric medulloblastoma. Sci Adv 2020;6:eabb5427.  Back to cited text no. 29
Azad TD, Jin MC, Bernhardt LJ, Bettegowda C. Liquid biopsy for pediatric diffuse midline glioma: A review of circulating tumor DNA and cerebrospinal fluid tumor DNA. Neurosurgical Focus 2020;48:E9.  Back to cited text no. 30
Mair R, Mouliere F, Smith CG, Chandrananda D, Gale D, Marass F, et al. Measurement of plasma cell-free mitochondrial tumor DNA improves detection of glioblastoma in patient-derived orthotopic xenograft models. Cancer Res 2019;79:220-30.  Back to cited text no. 31
Shen SY, Singhania R, Fehringer G, Chakravarthy A, Roehrl MHA, Chadwick D, et al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature 2018;563:579-83.  Back to cited text no. 32
Mouliere F, Chandrananda D, Piskorz AM, Moore EK, Morris J, Ahlborn LB, et al. Enhanced detection of circulating tumor DNA by fragment size analysis. Sci Transl Med 2018;10:eaat4921.  Back to cited text no. 33
Nassiri F, Chakravarthy A, Feng S, Shen SY, Nejad R, Zuccato JA, et al. Detection and discrimination of intracranial tumors using plasma cell-free DNA methylomes. Nat Med 2020;26:1044-7.  Back to cited text no. 34
Bagley SJ, Till J, Abdalla A, Sangha HK, Yee SS, Freedman J, et al. Association of plasma cell-free DNA with survival in patients with IDH wild-type glioblastoma. Neurooncol Adv 2021;3:vdab011. doi: 10.1093/noajnl/vdab011.  Back to cited text no. 35
Zill OA, Banks KC, Fairclough SR, Mortimer SA, Vowles JV, Mokhtari R, et al. The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients. Clin Cancer Res 2018;24:3528-38.  Back to cited text no. 36
Fontanilles M, Marguet F, Beaussire L, Magne N, Pépin LF, Alexandru C, et al. Cell-free DNA and circulating TERT promoter mutation for disease monitoring in newly-diagnosed glioblastoma. Acta Neuropathol Commun 2020;8:1-10. doi: 10.1186/s40478-020-01057-7.  Back to cited text no. 37
Schwaederle M, Husain H, Fanta PT, Piccioni DE, Kesari S, Schwab RB, et al. Detection rate of actionable mutations in diverse cancers using a biopsy-free (blood) circulating tumor cell DNA assay. Oncotarget 2016;7:9707-17.  Back to cited text no. 38
Mouliere F, Mair R, Chandrananda D, Marass F, Smith CG, Su J, et al. Detection of cell-free DNA fragmentation and copy number alterations in cerebrospinal fluid from glioma patients. EMBO Mol Med 2018;10:e9323. doi: 10.15252/emmm. 201809323.  Back to cited text no. 39
Martínez-Ricarte F, Mayor R, Martínez-Sáez E, Rubio-Pérez C, Pineda E, Cordero E, et al. Molecular diagnosis of diffuse gliomas through sequencing of cell-free circulating tumor DNA from cerebrospinal fluid. Clin Cancer Res 2018;24:2812-9.  Back to cited text no. 40
Pan C, Wu Y, Xiao X, Jiang L, Geng Y, Xu C, et al. Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA. Acta Neuropathol 2019;137:297-306.  Back to cited text no. 41
Miller AM, Shah RH, Pentsova EI, Pourmaleki M, Briggs S, Distefano N, et al. Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid. Nature 2019;565:654-8.  Back to cited text no. 42
Williams EA, Miller JJ, Tummala SS, Penson T, Iafrate AJ, Juratli TA, et al. TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations. Acta Neuropathol Commun 2018;6:106.  Back to cited text no. 43
Juratli TA, Stasik S, Zolal A, Schuster C, Richter S, Daubner D, et al. TERT promoter mutation detection in cell-free tumor-derived DNA in patients with IDH wild-type glioblastomas: A pilot prospective study. Clin Cancer Res 2018;24:5282-91.  Back to cited text no. 44
Huang TY, Piunti A, Lulla RR, Qi J, Horbinski CM, Tomita T, et al. Genetic Profiling of Circulating Free DNA in Glioma by Targeted Next Generation Sequencing. in Laboratory Investigation 2020;100:1610-1.  Back to cited text no. 45
Wang Y, Springer S, Zhang M, McMahon KW, Kinde I, Dobbyn L, et al. Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord. PNAS 2015;112:9704-9.  Back to cited text no. 46
García-Romero N, Carrión-Navarro J, Areal-Hidalgo P, Ortiz de Mendivil A, Asensi-Puig A, Madurga R, et al. BRAF V600E detection in liquid biopsies from pediatric central nervous system tumors. Cancers 209;12:66.  Back to cited text no. 47
Panditharatna E, Kilburn LB, Aboian MS, Kambhampati M, Gordish-Dressman H, Magge SN, et al. Clinically relevant and minimally invasive tumor surveillance of pediatric diffuse midline gliomas using patient-derived liquid biopsy. Clin Cancer Res 2018;24:5850-9.  Back to cited text no. 48
Hattori K, Sakata-Yanagimoto M, Suehara Y, Yokoyama Y, Kato T, Kurita N, et al. Clinical significance of disease-specific MYD88 mutations in circulating DNA in primary central nervous system lymphoma. Cancer Sci 2018;109:225-30.  Back to cited text no. 49
Fiano V, Trevisan M, Trevisan E, Senetta R, Castiglione A, Sacerdote C, et al. MGMT promoter methylation in plasma of glioma patients receiving temozolomide. J Neurooncol 2014;117:347-57.  Back to cited text no. 50
Sabedot TS, Malta TM, Snyder J, Nelson K, Wells M, deCarvalho AC, et al. A serum-based DNA methylation assay provides accurate detection of glioma. Neuro-Oncology 2021;23:1494-508.  Back to cited text no. 51
AbboshC, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution. Nature 2017;545:446-51.  Back to cited text no. 52
Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D, et al. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med 2012;4:162ra154-162ra154. doi: 10.1126/scitranslmed. 3004742.  Back to cited text no. 53
Lebofsky R, Decraene C, Bernard V, Kamal M, Blin A, Leroy Q, et al. Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping and personalized medicine in a prospective trial across all tumor types. Mol Oncol 2015;9:783-90.  Back to cited text no. 54
Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013;497:108-12.  Back to cited text no. 55
Oxnard GR, Paweletz CP, Kuang Y, Mach SL, O'Connell A, Messineo MM, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res 2014;20:1698-705.  Back to cited text no. 56
Rothwell DG, Ayub M, Cook N, Thistlethwaite F, Carter L, Dean E, et al. Utility of ctDNA to support patient selection for early phase clinical trials: The TARGET study. Nat Med 2019;25:738-43.  Back to cited text no. 57
Husain N, Mishra S, Husain A, Kaif M, Awale R, Shukla S. Genetic Profiling of Circulating Free DNA in Glioma by Targeted Next Generation Sequencing. In Laboratory Investigation 2020;100 (SUPPL 1):1610-1.  Back to cited text no. 58
Izquierdo E, Proszek P, Pericoli G, Temelso S, Clarke M, Carvalho DM, et al. Droplet digital PCR-based detection of circulating tumor DNA from pediatric high grade and diffuse midline glioma patients. Neuro Oncol Adv 2021;3:vdab013. doi: 10.1093/noajnl/vdab013.  Back to cited text no. 59
Raymond CK Hernandez J, Karr R, Hill K, Li M. Collection of cell-free DNA for genomic analysis of solid tumors in a clinical laboratory setting. PLoS One 2017;12:e0176241.  Back to cited text no. 60
Chen J, Huan W, Zuo H, Zhao L, Huang C, Liu X, et al. Alu methylation serves as a biomarker for non-invasive diagnosis of glioma. Oncotarget 2016;7:26099-106.  Back to cited text no. 61
Smirniotopoulos JG, Goldstein SJ. Differential Diagnosis of Brain Masses. In: Hodler J, von Schulthess GK, Zollikofer ChL, editors. Diseases of the Brain, Head & Neck, Spine 2012–2015. Milano: Springer Milan; 2012:16-20.  Back to cited text no. 62
von Baumgarten L, Illerhaus G, Korfel A, Schlegel U, Deckert M, Dreyling M. The diagnosis and treatment of primary CNS lymphoma. Dtsch Arztebl Int 2018;115:419-26.  Back to cited text no. 63
Fontanilles M, Duran-Peña A, Idbaih A. liquid biopsy in primary brain tumors: Looking for stardust! Curr Neurol Neurosci Rep 2018;18:13.  Back to cited text no. 64
Rimelen V, Ahle G, Pencreach E, Zinniger N, Debliquis A, Zalmaï L, et al. Tumor cell-free DNA detection in CSF for primary CNS lymphoma diagnosis. Acta Neuropathol Commun 2019;7:43.  Back to cited text no. 65
Nichols AC, Lowes LE, Szeto CC, Basmaji J, Dhaliwal S, Chapeskie C, et al. Detection of circulating tumor cells in advanced head and neck cancer using the cellsearch system. Head Neck 2012;34:1440-4.  Back to cited text no. 66
Swaby RF, Cristofanilli M. Circulating tumor cells in breast cancer: A tool whose time has come of age. BMC Medicine 2011;9:43.  Back to cited text no. 67
O'Flaherty JD, Gray S, Richard D, Fennell D, O'Leary JJ, Blackhall FH, et al. Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer. Lung Cancer 2012;76:19-25.  Back to cited text no. 68
Takeuchi H, Kitagawa Y. Circulating tumor cells in gastrointestinal cancer. J Hepatobiliary Pancreat Sci 2010;17:577-82.  Back to cited text no. 69
Kruck S, Gakis G, Stenzl A. Disseminated and circulating tumor cells for monitoring chemotherapy in urological tumors. Anticancer Res 2011;31:2053-7.  Back to cited text no. 70
Awasthi NP, Kumari S, Neyaz A, Gupta S, Agarwal A, Singhal A, et al. EpCAM-based flow cytometric detection of circulating tumor cells in gallbladder carcinoma cases. Asian Pac J Cancer Prev 2017;18:3429-37.  Back to cited text no. 71
Adamczyk LA, Williams H, Frankow A, Ellis HP, Haynes HR, Perks C, et al. Current understanding of circulating tumor cells – potential value in malignancies of the central nervous system. Front Neurol 2015;6:174.  Back to cited text no. 72
Müller C, Holtschmidt J, Auer M, Heitzer E, Lamszus K, Schulte A, et al. Hematogenous dissemination of glioblastoma multiforme. Sci Transl Med 2014;6:247ra101.  Back to cited text no. 73
Pratt ED, Huang C, Hawkins BG, Gleghorn JP, Kirby BJ. Rare cell capture in microfluidic devices. Chem Eng Sci 2011;66:1508-22.  Back to cited text no. 74
Sullivan JP, Nahed BV, Madden MW, Oliveira SM, Springer S, Bhere D, et al. Brain tumor cells in circulation are enriched for mesenchymal gene expression. Cancer Discov 2014;4:1299-309.  Back to cited text no. 75
Gao F, Cui Y, Jiang H, Sui D, Wang Y, Jiang Z, et al. Circulating tumor cell is a common property of brain glioma and promotes the monitoring system. Oncotarget 2016;7:71330-40.  Back to cited text no. 76
Bang-Christensen SR, Pedersen RS, Pereira MA, Clausen TM, Løppke C, Sand NT, et al. Capture and detection of circulating glioma cells using the recombinant VAR2CSA malaria protein. Cells 2019;8:998.  Back to cited text no. 77
Liu T, Xu H, Huang M, Ma W, Saxena D, Lustig RA, et al. Circulating glioma cells exhibit stem cell-like properties. Cancer Res 2018;78:6632-42.  Back to cited text no. 78
Nayak L, Fleisher M, Gonzalez-Espinoza R, Lin O, Panageas K, Reiner A, et al. Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors. Neurology 2013;80:1598-605.  Back to cited text no. 79
Lin X, Fleisher M, Rosenblum M, Lin O, Boire A, Briggs S, et al. Cerebrospinal fluid circulating tumor cells: A novel tool to diagnose leptomeningeal metastases from epithelial tumors. Neuro Oncol 2017;19:1248-54.  Back to cited text no. 80
Shankar GM, Balaj L, Stott SL, Nahed B, Carter BS. Liquid biopsy for brain tumors. Exp Rev Mol Diagn 2017;17:943-7.  Back to cited text no. 81
Guerreiro Stucklin AS, Ramaswamy V, Daniels C, Taylor MD. Review of molecular classification and treatment implications of pediatric brain tumors. Curr Opin Pediatr 2018;30:3-9.  Back to cited text no. 82
Heller G, McCormack R, Kheoh T, Molina A, Smith MR, Dreicer R, et al. Circulating tumor cell number as a response measure of prolonged survival for metastatic castration-resistant prostate cancer: A comparison with prostate-specific antigen across five randomized phase III clinical trials. J Clin Oncol 2018;36:572-80.  Back to cited text no. 83
Zhao Y, Jiang F, Wang Q, Wang B, Han Y, Yang J, et al. Cytoplasm protein GFAP magnetic beads construction and application as cell separation target for brain tumors. J Nanobiotechnology 2020;18:169.  Back to cited text no. 84
MacArthur KM, Kao GD, Chandrasekaran S, Alonso-Basanta M, Chapman C, Lustig RA, et al. Detection of brain tumor cells in the peripheral blood by a telomerase promoter-based assay. Cancer Res 2014;74:2152-9.  Back to cited text no. 85
Krol I, Castro-Giner F, Maurer M, Gkountela S, Szczerba BM, Scherrer R, et al. Detection of circulating tumour cell clusters in human glioblastoma. Br J Cancer 2018;119:487-91.  Back to cited text no. 86
Liu A, Hou C, Chen H, Zong X, Zong P. Genetics and epigenetics of glioblastoma: Applications and overall incidence of IDH1 mutation. Front Oncol 2016;6. doi: 10.3389/fonc. 2016.00016.  Back to cited text no. 87
Floyd D, Purow B. Micro-masters of glioblastoma biology and therapy: Increasingly recognized roles for microRNAs. Neuro Oncol 2014;16:622-7.  Back to cited text no. 88
Hayes J, Peruzzi PP, Lawler S. MicroRNAs in cancer: Biomarkers, functions and therapy. Trends Mol Med 2014;20:460-9.  Back to cited text no. 89
Wang Q, Li P, Li A, Jiang W, Wang H, Wang J, et al. Plasma specific miRNAs as predictive biomarkers for diagnosis and prognosis of glioma. J Exp Clin Cancer Res 2012;31:97.  Back to cited text no. 90
Qu K, Lin T, Pang Q, Liu T, Wang Z, Tai M, et al. Extracellular miRNA-21 as a novel biomarker in glioma: Evidence from meta-analysis, clinical validation and experimental investigations. Oncotarget 2016;7:33994-4010.  Back to cited text no. 91
Ma C, Nguyen HPT, Luwor RB, Stylli SS, Gogos A, Paradiso L, et al. A comprehensive meta-analysis of circulation miRNAs in glioma as potential diagnostic biomarker. PloS One 2018;13:e0189452.  Back to cited text no. 92
Morokoff A, Jones J, Nguyen H, Ma C, Lasocki A, Gaillard F, et al. Serum microRNA is a biomarker for post-operative monitoring in glioma. J Neurooncol 2020;149:391-400.  Back to cited text no. 93
Manterola L, Guruceaga E, Gállego Pérez-Larraya J, González-Huarriz M, Jauregui P, Tejada S, et al. A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro Oncol 2014;16:520-7.  Back to cited text no. 94
Zhao H, Shen J, Hodges TR, Song R, Fuller GN, Heimberger AB. Serum microRNA profiling in patients with glioblastoma: A survival analysis. Mol Cancer 2017;16:59.  Back to cited text no. 95
Ebrahimkhani S, Vafaee F, Hallal S, Wei H, Lee MYT, Young PE, et al. Deep sequencing of circulating exosomal microRNA allows non-invasive glioblastoma diagnosis. NPJ Precis Oncol 2018;2:28.  Back to cited text no. 96
Swellam M, Ezz El Arab L, Al-Posttany AS, Said SB. Clinical impact of circulating oncogenic MiRNA-221 and MiRNA-222 in glioblastoma multiform. J Neurooncol 2019;144:545-51.  Back to cited text no. 97
Roth P, Wischhusen J, Happold C, Chandran PA, Hofer S, Eisele G, et al. A specific miRNA signature in the peripheral blood of glioblastoma patients. J Neurochem 2011;118:449-57.  Back to cited text no. 98
Regazzo G, Terrenato I, Spagnuolo M, Carosi M, Cognetti G, Cicchillitti L, et al. A restricted signature of serum miRNAs distinguishes glioblastoma from lower grade gliomas. J Exp Clin Cancer Res 2016;35:124.  Back to cited text no. 99
Ivo D'Urso P, Fernando D'Urso O, Damiano Gianfreda C, Mezzolla V, Storelli C, Marsigliante S. miR-15b and miR-21 as circulating biomarkers for diagnosis of glioma. Curr Genomics 2015;16:304-11.  Back to cited text no. 100
Zhang R, Pang B, Xin T, Guo H, Xing Y, Xu S, et al. Plasma miR-221/222 family as novel descriptive and prognostic biomarkers for glioma. Mol Neurobiol 2016;53:1452-60.  Back to cited text no. 101
Shao N, Wang L, Xue L, Wang R, Lan Q. Plasma miR-454-3p as a potential prognostic indicator in human glioma. Neurol Sci 2015;36:309-13.  Back to cited text no. 102
Xiao Y, Zhang L, Song Z, Guo C, Zhu J, Li Z, Zhu S. Potential diagnostic and prognostic value of plasma circulating MicroRNA-182 in human glioma. Med Sci Monit 2016;22:855-62.  Back to cited text no. 103
Lai NS, Wu DG, Fang XG, Lin YC, Chen SS, Li ZB–, et al. Serum microRNA-210 as a potential noninvasive biomarker for the diagnosis and prognosis of glioma. Br J Cancer 2015;112:1241-6.  Back to cited text no. 104
Siegal T, Charbit H, Paldor I, Zelikovitch B, Canello T, Benis A, et al. Dynamics of circulating hypoxia-mediated miRNAs and tumor response in patients with high-grade glioma treated with bevacizumab. J Neurosurg 2016;125:1008-15.  Back to cited text no. 105
Wu J, Li L, Jiang C. Identification and evaluation of serum MicroRNA-29 family for glioma screening. Mol Neurobiol 2015;52:1540-6.  Back to cited text no. 106
Sun J, Liao K, Wu X, Huang J, Zhang S, Lu X. Serum microRNA-128 as a biomarker for diagnosis of glioma. Int J Clin Exp Med 2015;8:456-63.  Back to cited text no. 107
Wei X, Chen D, Lv T, Li G, Qu S. Serum MicroRNA-125b as a potential biomarker for glioma diagnosis. Mol Neurobiol 2016;53:163-70.  Back to cited text no. 108
Yue X, Lan F, Hu M, Pan Q, Wang Q, Wang J. Downregulation of serum microRNA-205 as a potential diagnostic and prognostic biomarker for human glioma. J Neurosurg 2016;124:122-8.  Back to cited text no. 109
Huang Q, Wang C, Hou Z, Wang G, Lv J, Wang H, et al. Serum microRNA-376 family as diagnostic and prognostic markers in human gliomas. Cancer Biomark 2017;19:137-44.  Back to cited text no. 110
Zhi F, Shao N, Wang R, Deng D, Xue L, Wang Q, et al. Identification of 9 serum microRNAs as potential noninvasive biomarkers of human astrocytoma. Neuro Oncol 2015;17:383-91.  Back to cited text no. 111
Yang C, Wang C, Chen X, Chen S, Zhang Y, Zhi F, et al. Identification of seven serum microRNAs from a genome-wide serum microRNA expression profile as potential noninvasive biomarkers for malignant astrocytomas. International journal of cancer. 2013;132:116-27.  Back to cited text no. 112
Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008;10:1470-6.  Back to cited text no. 113
Figueroa J, Phillips LM, Shahar T, Hossain A, Gumin J, Kim H, et al. Exosomes from glioma-associated mesenchymal stem cells increase the tumorigenicity of glioma stem-like cells via transfer of miR-1587. Cancer Res 2017;77:5808-19.  Back to cited text no. 114
Noerholm M, Balaj L, Limperg T, Salehi A, Zhu LD, Hochberg FH, et al. RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls. BMC Cancer 2012;12:22.  Back to cited text no. 115
Osti D, Del Bene M, Rappa G, Santos M, Matafora V, Richichi C, et al. Clinical significance of extracellular vesicles in plasma from glioblastoma patients. Clin Cancer Res 2019;25:266-76.  Back to cited text no. 116
Chen WW, Balaj L, Liau LM, Samuels ML, Kotsopoulos SK, Maguire CA, et al. BEAMing and droplet digital PCR analysis of mutant IDH1 mRNA in glioma patient serum and cerebrospinal fluid extracellular vesicles. Mol Ther Nucleic Acids 2013;2:e109.  Back to cited text no. 117
Fraser K, Jo A, Giedt J, Vinegoni C, Yang KS, Peruzzi P, et al. Characterization of single microvesicles in plasma from glioblastoma patients. Neuro Oncol 2019;21:606-15.  Back to cited text no. 118
Roy S, Hochberg FH, Jones PS. Extracellular vesicles: The growth as diagnostics and therapeutics; a survey. J Extracell Vesicles 2018;7:1438720. doi: 10.1080/20013078.2018.1438720.  Back to cited text no. 119
Ji Y, Qi D, Li L, Su H, Li X, Luo Y, et al. Multiplexed profiling of single-cell extracellular vesicles secretion. PNAS 2019;116:5979-84.  Back to cited text no. 120
Mallawaaratchy DM, Hallal S, Russell B, Ly L, Ebrahimkhani S, Wei H, et al. Comprehensive proteome profiling of glioblastoma-derived extracellular vesicles identifies markers for more aggressive disease. J Neurooncol 2017;131:233-44.  Back to cited text no. 121
Gollapalli K, Ray S, Srivastava R, Renu D, Singh P, Dhali S, et al. Investigation of serum proteome alterations in human glioblastoma multiforme. Proteomics 2012;12:2378-90.  Back to cited text no. 122
Kumar DM, Thota B, Shinde SV, Prasanna KV, Hegde AS, Arivazhagan A, et al. Proteomic identification of haptoglobin α2 as a glioblastoma serum biomarker: Implications in cancer cell migration and tumor growth. J Proteome Res 2010;9:5557-67.  Back to cited text no. 123
Qin G, Li X, Chen Z, Liao G, Su Y, Chen Y, et al. Prognostic value of YKL-40 in patients with glioblastoma: A systematic review and meta-analysis. Mol Neurobiol 2017;54:3264-70.  Back to cited text no. 124
Iwamoto FM, Hottinger AF, Karimi S, Riedel E, Dantis J, Jahdi M, et al. Serum YKL-40 is a marker of prognosis and disease status in high-grade gliomas. Neuro-Oncology 2011;13:1244-51.  Back to cited text no. 125
Petrik V, Saadoun S, Loosemore A, Hobbs J, Opstad KS, Sheldon J, et al. Serum α2-HS glycoprotein predicts survival in patients with glioblastoma. Clin Chem 2008;54:713-22.  Back to cited text no. 126
van Linde ME, van der Mijn JC, Pham TV, Knol JC, Wedekind LE, Hovinga KE, et al. Evaluation of potential circulating biomarkers for prediction of response to chemoradiation in patients with glioblastoma. J Neurooncol 2016;129:221-30.  Back to cited text no. 127
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009;462:739-44.  Back to cited text no. 128
Björkblom B, Jonsson P, Tabatabaei P, Bergström P, Johansson M, Asklund T, et al. Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma. Br J Cancer 2020;122:221-32.  Back to cited text no. 129

Correspondence Address:
Nuzhat Husain
Professor and Head, Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow - 226 010, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_1058_21

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