 Abstract | | |
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 | |  |
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 | | |
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
Click here to view |
| Cell-Free DNA (CfDNA) | | |
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
Click here to view |
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]
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 | | |
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].
| Circulating microRNA | | |
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]
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 | | |
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 | | |
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 | | |
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.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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Correspondence Address:
Nuzhat Husain
Professor and Head, Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow - 226 010, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijpm.ijpm_1058_21
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3] |
