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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 179-187

Role of liquid biopsy in central nervous system tumors


Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication02-Nov-2021

Correspondence Address:
Dr. Chitra Sarkar
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_425_21

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  Abstract 


Challenges in obtaining tissue specimens and tumor heterogeneity are major limitations for accurate diagnosis, molecular characterization, risk stratification, and development of biomarker-driven therapies in central nervous system (CNS) tumors. The potential of assessment of CNS tumors through analysis of corporeal fluids (liquid biopsy) is being explored to document tumor-related genetic/epigenetic alterations and protein expression to identify prognostic and therapeutic biomarkers. The quantity of circulating tumor DNA isolated also appears to be directly associated with tumor progression and response to treatment. In this review, we provide synopsis of the recent studies which have provided crucial insights into analyzing circulating tumor cells, cell-free nucleic acids, and extracellular vesicles for directing long-term disease control. We have also highlighted the stumbling blocks and gaps in technology that need to be overcome to translate research findings into a tool in the clinical setting.

Keywords: Liquid biopsy, cfDNA, ctDNA


How to cite this article:
Chakraborty R, Suri V, Dandapath I, Singh J, Sharma M C, Sarkar C. Role of liquid biopsy in central nervous system tumors. Int J Neurooncol 2021;4, Suppl S1:179-87

How to cite this URL:
Chakraborty R, Suri V, Dandapath I, Singh J, Sharma M C, Sarkar C. Role of liquid biopsy in central nervous system tumors. Int J Neurooncol [serial online] 2021 [cited 2021 Nov 27];4, Suppl S1:179-87. Available from: https://www.Internationaljneurooncology.com/text.asp?2021/4/3/179/329820




  Introduction Top


The evaluation of molecular genetic alterations in cancers is nowadays very important for diagnosis, prognostication, management, and treatment decisions, as well as assessment of treatment responses, treatment resistance, and relapse. Molecular profiling is generally done on resected or biopsy specimen of primary tumors. The main limitation of such analysis is that tissue biopsy/resection is a single fixed time point evaluation. Serial monitoring of tumor progression and evolution and dynamic follow-up of modifications in molecular alterations cannot be done on tissue biopsies/resections since these require surgical intervention, are invasive procedures and therefore not easily available. Further, formalin-fixed paraffin-embedded tissues present lot of variability in the quantity and quality of DNA and RNA depending on procedures of collection, storage, and preservation.[1],[2]

To circumvent such practical issues, liquid biopsies are becoming of increasing interest since they can be obtained by minimally invasive procedures. They allow real-time systematic and dynamic monitoring of molecular alterations in cancer patients as they can be done repeatedly. Hence, they are very useful for detecting, analyzing, and monitoring diagnostic, prognostic, and predictive cancer biomarkers at pretreatment, treatment, and posttreatment levels. Thus, they help in monitoring response to treatment as well as assessment of treatment resistance and disease relapse. [1],[2]

Liquid biopsies utilize liquid samples such as blood, urine, saliva, stool, and other biological material which can be obtained by minimally invasive techniques such as ascites fluid and cerebrospinal fluid (CSF).[3]

The biomarkers assessed in liquid biopsy include cell-free DNA (cfDNA), cell-free RNA, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), tumor educated platelet, exosomes, proteins, and microRNA.[3]

CTCs are cancer cells that get detached from the primary tumor and/or metastatic lesion and travel by the bloodstream to other parts of the body. They comprise of DNA, RNA, and protein from tumors. Their number is very low (<10 cells per 1 ml of blood) and their half-life is also short (1–2.4 h.). Hence, CTC is tedious to isolate owing to their variable properties including size, clustering capability, and varied cell surface markers. However, they can be used to perform genomic and transcriptomic analysis in cancers. Certain innovative culturing approaches have also been developed to perform functional studies using these cells, including therapy testing, developing xenograft models, and three-dimensional tissues. As of 2018, CELL SEARCH CTC test based on the expression of epithelial cell adhesion molecule and the lack of CD45 on the cell surface is the only United States Food and Drug Administration approved CTC quantification platform. It is being used for metastatic prostate, breast, and colorectal cancers. [1],[2],[3]

cfDNA is released in liquid samples through secretion, apoptosis, or necrosis from cells in the body. The cfDNA concentration is approximately 1–10 ng/ml in the plasma. The tumor-derived DNA can be detected within this cfDNA fraction of blood and other liquid samples from patients with cancer. This is called ctDNA and its concentration can be <0.1% of the cfDNA. The difference between ctDNA and nontumor-derived cfDNA is that the former comprises of 134–144 bp DNA fragments versus 167 bp fragments in the latter. The main challenge of using ctDNA is to develop sufficiently sensitive assays for differentiating low ctDNA signals from high cfDNA background level.[3] The methods used for cfDNA analysis include quantitative polymerase chain reaction (PCR), digital PCR, and next-generation sequencing (NGS).[3]

Exosomes are used for analysis of nucleic acids in liquid biopsies. They are 42–200 mm in diameter and their content includes DNA, mRNA, microRNA, and protein. They are secreted from multivesicular bodies by the process of exocytosis in live cells. However, their method of isolation is laborious and it may be difficult to differentiate between tumor-derived exosomes and normal cells.[3]

Uses of liquid biopsy

  1. For early detection/diagnosis of cancer. This requires that specific DNA mutations are identified and validated as drivers for early-stage cancer
  2. To monitor minimal residual disease (MRD) – MRD measurement can be very important in recognizing patients with a high chance of relapse, especially in the absence of other biomarkers
  3. Assessment of tumor mutation burden (TMB) – TMB is defined as the total number of mutations per coding region of the genome. High TMB is an emerging predictor of sensitivity to immune checkpoint such as programmed death 1 or its ligand programmed death-ligand 1
  4. For dynamic follow-up of cancer case – follow-up after surgery, early assessment of therapeutic efficacy, diagnosis of relapse, identification of treatment resistance.


Liquid biopsy especially cfDNA analysis has entered the clinic for cancer management especially for non-small cell lung, breast, and colorectal cancers. The use of liquid biopsy has exponentially increased since 2010 but the primary bottleneck remains the technical difficulty for establishing sensitive technologies to measure cfDNA circulating in the blood. The technical difficulties range from collection of specimens to storage as well as detection methodologies. More validation is required to elucidate that molecular markers detected from liquid biopsy match the markers from classical tissue tumor biopsy. New technology platforms need to be developed for reducing cost, improving quality as well as speed of detection, before liquid biopsy becomes accepted as the point-of-care testing in cancer patients. [1],[3]

The next section will deal with liquid biopsy application in central nervous system (CNS) tumors. Although not very successful till date, numerous studies are ongoing and we hope to use it to monitor CNS tumors in the near future.

Liquid biopsy in central nervous system tumors

Biopsies in the brain are very challenging as many CNS tumors are not amenable to surgical resection, either due to sensitive neuroanatomical location or the infiltrating nature of the tumor, which at times are an issue for even the most competent neurosurgeons.[4],[5] Furthermore, owing to regional heterogeneity, the sampling of a lesion by biopsy may not be able to identify mutations present across all regions of a tumor.[6] The identification of a reliable biomarker in accessible body fluids would be useful for diagnosis, prognosis, and follow-up in CNS tumors. Thus, a liquid biopsy would facilitate following up patients in a longitudinal fashion after the initial diagnosis and treatment as well as to fully capture the intratumoral heterogeneity.[4],[7]

Most commonly used liquid biopsy specimens for CNS tumors are serum and urine as these samples are easy to collect, but they have low content of ctDNA and CTC, which could mainly be due to the blood–brain barrier.[8],[9] Sampling of CSF through lumbar puncture has higher amount of nucleic acid content.[10],[11] However, it has some limitations. Many patients with brain tumors present with raised intracranial pressure wherein lumbar puncture is contraindicated.[12] Technical issues such as blood contamination in the CSF sample are also possible. A CSF-based liquid biopsy may not be appropriate for intra-axial CNS tumors, which lack any association with the CSF.[13]

Several molecular alterations of strong diagnostic, prognostic, or predictive significance have been assessed in CNS tumors using several tumor-derived circulating nucleic acids (e.g. ctDNA, cmtDNA, mRNA, noncoding RNAs), or CTCs predominantly from serum or CSF samples.[8] Advanced technologies such as droplet-based digital polymerase chain reaction (ddPCR) and NGS have significantly enhanced the sensitivity and specificity for the detection of these alterations.[14] NGS facilitates exploring a wide range of possible new mutations while ddPCR can be used for detecting known specific mutations.[15],[16] The present article reviews the important alterations analyzed for differential diagnosis, patient stratification, and follow-up in CNS tumors. Although mostly conducted in gliomas, some recent studies on other CNS tumors are also available.


  Diffuse Gliomas Top


Isocitrate dehydrogenase mutations1/2

Isocitrate dehydrogenase (IDH) mutation is present in ~80% of Grades II–IV astrocytomas and all oligodendrogliomas.[17] IDH1/2 mutations are now part of the routine diagnostic pipeline and bear prognostic relevance as IDH-mutant gliomas have better prognosis compared to IDH wild type. [18],[19] Majority of cases harbor IDH1 mutation restricted to amino acid residue 132, with >85% containing a heterozygous missense mutation of arginine to histidine (R132H).[20]

Boisselier et al., analyzed IDH R132H mutation in plasma ctDNA using a combination of coamplification and digital PCR with 100% specificity. Sensitivity was 60% for the whole series but 70% for patients with the WHO high-grade gliomas (HGGs) and 100% in HGGs with an enhancing tumor volume higher than 3.5 cm3. However, a poor sensitivity of 37.5% was observed for low-grade gliomas.[21]

Chen et al., validated IDH1 mRNA transcripts within CSF of patients, using BEAMing (beads, emulsion, amplification, magnetics) and ddPCR with a sensitivity of 63% and a specificity of 100%.[22] Using targeted sequencing, sensitivity of IDH mutation detection has been documented to be more than 80% for CSF while the sensitivity is far less with plasma ctDNA.[23],[24],[25],[26],[27]

Methylguanine-DNA methyltransferase promoter methylation

Epigenetic silencing of the methylguanine-DNA methyltransferase promoter (MGMT) gene through methylation of promoter CpGs has been observed in 48%–75% [wild type] IDH-mutant Grades II-IV astrocytomas and 36% IDHwt glioblastomas (GBMs).[28] MGMT promoter methylation impairs DNA repair and predicts better treatment response with alkylating agents and longer survival in patients with GBM.[29] Elderly GBM patients eligible for either radiotherapy (RT) or temozolomide (TMZ) should be tested for MGMT promoter methylation before undertaking therapeutic decision.[30],[31] Further, MGMT promoter methylation helps to differentiate true progression from pseudoprogression in patients with newly diagnosed GBM treated with surgery followed by radiochemotherapy.[32]

Using both tumor and serum DNA, Balaña et al. analyzed MGMT methylation in 28 GBM patients treated with BCNU or with TMZ plus cisplatin, by methylation-specific PCR (MS PCR). High concordance was found between cfDNA and the tumor tissue samples.[33] An average sensitivity of 65% in CSF and 1%–50% in plasma has been observed using MS PCR.[34],[35],[36],[37] Applying methylated DNA immunoprecipitation, positive rates of MGMT promoter methylation in tumor tissue, serum, and CSF were 97.0%, 71.2%, and 78.8%, respectively.[38]

Telomerase reverse transcriptase promoter mutations

Telomerase reverse transcriptase (TERT) promoter mutations (pTERTs) are among the most common genetic alterations in gliomas and are associated with dismal prognosis in IDH wild-type diffuse astrocytomas (DAs) and in GBMs irrespective of IDH status.[39] Two recurrent mutually exclusive mutations in pTERT region, C228T and C250T, are seen in 18%–40% of Grades II/III IDH-wt DAs and 70%–80% of all GBMs.[39],[40],[41],[42] Consortium to inform molecular and practical approaches to CNS tumor taxonomy (cIMPACT-NOW) Updates recommend reclassifying IDH-wt Grades II/III DAs harboring pTERT mutation as GBMs.[43] Different strategies to target pTERT activity, such as small molecule inhibitor, immunotherapy, and vaccines are being investigated.[44],[45],[46] Detecting pTERT mutations in CSF or plasma ctDNA is crucial for diagnosis and to monitor and assess response to therapy.

In a pilot study by Juratli et al., using NGS and ddPCR (for validation) platforms, pTERT mutation in the CSF-ctDNA was detected with 100% specificity and 92.1% sensitivity. However, the sensitivity in the plasma ctDNA was 7.9%.[47] An increasing pTERT mutation variant allele frequency levels in the CSF-tDNA were observed in patients with unfavorable outcomes. Similarly, Fontanilles et al., analyzed 49 glioblastomas and 3 gliosarcomas by ddPCR and observed pTERT in plasma ctDNA in only 3.8% of cases.[48] The authors suggested that the short size of the ctDNA fragments (<70 bp) was the primary factor related to failure of pTERT mutation detection in plasma.[48],[49] Interestingly, the authors documented that the cfDNA concentration varies significantly over the course of treatment and may be a biomarker of progression during the TMZ phase. Using 7-deaza-dGTP as a ddPCR additive and utilizing standardized handling strategies and technical optimization, Muralidharan et al., (2021) reported an overall sensitivity of 62.5% and specificity of 90% in ctDNA in plasma.[50]

Epidermal growth factor receptor

Epidermal growth factor receptor (EGFR) (7p12) amplification, overexpression, and/or mutations are commonly seen in IDHwt GBMs.[51] The evidence for EGFR amplification or EGFRvIII mutation as independent predictive markers for survival in GBM varies among different studies.[52],[53],[54],[55] An ongoing trial of the EGFRvIII vaccine (Rindopepimut) CDX-110 has shown longer overall survival in GBM patients treated after tumor resection.[56] Using qPCR, a sensitivity of 61% and a specificity of 98% were observed in CSF-derived extracellular vesicles (EVs) to detect EGFRvIII-positive GBMs.[57] Overall, sensitivity and specificity of semiquantitative exosome EGFRvIII PCR assay in serum were 81.58% and 79.31%.[58]

TP53 and PTEN mutations

The WHO Grades II and III, IDH-mutant astrocytic tumors frequently carry TP53 mutations (>80%).[59] Deletions and mutations in the tumor suppressor gene PTEN are frequent events (~35%) in GBMs. Loss of PTEN is associated with poor survival and therapeutic resistance in GBMs.[60],[61] In a recent study by Zhao et al., on 17 pairs of matched CSF and tumor samples from patients with gliomas, mutations of PTEN and TP53 were commonly detected in CSF ctDNA of recurrent glioma patients.[23]

H3K27M mutation

Somatic driver mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, are seen dominantly in pediatric high-grade infiltrative astrocytomas arising within midline structures (thalamus, brain stem, and spinal cord) and are associated with very poor outcome (median OS: 9–11 months).[62],[63],[64] DMG, H3K27M mutant was introduced as a new diagnostic entity in the updated 2016 WHO classification of CNS tumors.[65],[66] The sensitive anatomic location and the need for specialized surgical expertise have limited the favorability of surgical biopsy, especially in recurrent cases. Although limited in sensitivity and specificity, MR imaging is still widely used to diagnose and assess response to therapy.[67],[68],[69]

In a study of 48 pediatric DMG patients, Panditharatna et al., (2018) using ddPCR detected H3K27M ctDNA in 87% of CSF samples and 90% of plasma samples analyzed from patients known to harbor oncohistones in their primary tumors. A significant decrease in H3K27M plasma ctDNA was observed in concordance with MRI assessment of tumor response to RT in 83% of patients.[70] Li et al., analyzed H3K27M mutation in DMG in ctDNA across two platforms of ddPCR (RainDance and BioRad) using CSF, plasma, and tumor specimens. The authors documented 100% sensitivity and specificity in matched tumor tissue and CSF samples. H3.3K27M mutation detection in blood specimens was most technically challenging owing to very low quantity of ctDNA. Vacuum-concentration and preamplification of ctDNA was employed to increase test sensitivity without decreasing specificity.[71]


  Medulloblastoma Top


Medulloblastoma (MB), an embryonal tumor of the CNS, is the most aggressive brain tumor in childhood that can also occur in adults, although less common.[72] It is a complex and evolving heterogeneous disease that can be divided into four molecular consensus subgroups (WNT, SHH, Group 3 and Group 4), with prognostic and therapeutic implications.[73],[74],[75],[76],[77] In a recent study by Escudero et al., on 13 pediatric MBs, ctDNA was more abundant in CSF (76.9% patients) than plasma (7.6% patients). Exome sequencing of CSF ctDNA recapitulated the tumor mutational burden and the genomic alterations, including MB common mutations (PTCH1, TP53), copy number variation (CNVs) (MYCN and GLI2 amplification), and arm-level chromosomal aberrations (chromosome 17p loss), providing diagnostic and prognostic information.[78] MB also harbors abnormal DNA methylation changes, with distinct epigenetic signatures identified across MB subtypes that can be altered during tumor progression and treatment.[74],[79] Li et al., 2020 identified reliable DNA methylation signatures in ctDNA of MB patients that have potential diagnostic and prognostic values.[80]


  Other Central Nervous System Tumors Top


Few studies have analyzed the role of liquid biopsy in other CNS tumors such as ependymoma and meningioma. However, substantial data are not available.[81],[82],[83] ctDNA has only been detected in the plasma of a minority of patients with CNS lymphoma.[84],[85] In contrast, several studies revealed that the analysis of CSF ctDNA better detects CNS disease in patients with B-cell lymphoma.[86],[87],[88],[89],[90],[91] [Table 1] elucidates the key molecular alterations in CNS tumors that have been assessed by liquid biopsy, platforms used for their identification, and sensitivity/specificity of these techniques.
Table 1: A summary of molecular alterations identified in central nervous system tumors using liquid biopsy

Click here to view



  Challenges and Future Directions Top


Liquid biopsy in CNS tumors can facilitate an early detection of relapse and identify therapeutic targets or mechanisms of resistance to adjust the therapeutic strategy at relapse. However, detection of ctDNA may be influenced by tumor burden, tumor progression, and anatomical location.[24],[82],[92] For analysis of specific mutations by sensitive techniques such as ddPCR, prior knowledge of the tumor genetic profile is required. Whole exome sequencing or targeted gene panels might provide more information. However, it is important to consider sensitivity, turnaround time, and cost-effectiveness. To determine the impact of the results and translate them into a tool for clinical practice, standardization of protocols and larger studies with more patients will be required. Altogether, liquid biopsy remains a promising strategy to improve the clinical management of patients with CNS malignancies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Poulet G, Massias J, Taly V. Liquid biopsy: General concepts. Acta Cytol 2019;63:449-55.  Back to cited text no. 1
    
2.
Kilgour E, Rothwell DG, Brady G, Dive C. Liquid biopsy-based biomarkers of treatment response and resistance. Cancer Cell 2020;37:485-95.  Back to cited text no. 2
    
3.
Chen D, Xu T, Wang S, Chang H, Yu T, Zhu Y, et al. Liquid biopsy applications in the clinic. Mol Diagn Ther 2020;24:125-32.  Back to cited text no. 3
    
4.
Shankar GM, Balaj L, Stott SL, Nahed B, Carter BS. Liquid biopsy for brain tumors. Expert Rev Mol Diagn 2017;17:943-7.  Back to cited text no. 4
    
5.
Bonner ER, Bornhorst M, Packer RJ, Nazarian J. Liquid biopsy for pediatric central nervous system tumors. NPJ Precis Oncol 2018;2:29.  Back to cited text no. 5
    
6.
Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883-92.  Back to cited text no. 6
    
7.
Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014;344:1396-401.  Back to cited text no. 7
    
8.
Siravegna G, Marsoni S, Siena S, Bardelli A. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol 2017;14:531-48.  Back to cited text no. 8
    
9.
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. 9
    
10.
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. Neurosurg Focus 2020;48:E9.  Back to cited text no. 10
    
11.
Redzic Z. Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: Similarities and differences. Fluids Barriers CNS 2011;8:3.  Back to cited text no. 11
    
12.
Yan W, Xu T, Zhu H, Yu J. Clinical applications of cerebrospinal fluid circulating tumor DNA as a liquid biopsy for central nervous system tumors. Onco Targets Ther 2020;13:719-31.  Back to cited text no. 12
    
13.
Seoane J, De Mattos-Arruda L, Le Rhun E, Bardelli A, Weller M. Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases. Ann Oncol 2019;30:211-8.  Back to cited text no. 13
    
14.
Postel M, Roosen A, Laurent-Puig P, Taly V, Wang-Renault SF. Droplet-based digital PCR and next generation sequencing for monitoring circulating tumor DNA: A cancer diagnostic perspective. Expert Rev Mol Diagn 2018;18:7-17.  Back to cited text no. 14
    
15.
Karlin-Neumann G. Improved liquid biopsies with combined digital PCR and next-generation sequencing. Am Lab Mag 2016;48:17-9.  Back to cited text no. 15
    
16.
Komatsubara KM, Sacher AG. Circulating tumor DNA as a liquid biopsy: Current clinical applicationsand future directions. Oncol (Williston Park. NY) 2017;31:618-27.  Back to cited text no. 16
    
17.
Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 2008;116:597-602.  Back to cited text no. 17
    
18.
Cohen AL, Holmen SL, Colman H. IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep 2013;13:345.  Back to cited text no. 18
    
19.
Agarwal S, Sharma MC, Jha P, Pathak P, Suri V, Sarkar C, et al. Comparative study of IDH1 mutations in gliomas by immunohistochemistry and DNA sequencing. Neuro Oncol 2013;15:718-26.  Back to cited text no. 19
    
20.
Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Seo SI, et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer 2019;125:353-5.  Back to cited text no. 20
    
21.
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. 21
    
22.
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. 22
    
23.
Zhao Z, Zhang C, Li M, Shen Y, Feng S, Liu J, et al. Applications of cerebrospinal fluid circulating tumor DNA in the diagnosis of gliomas. Jpn J Clin Oncol 2020;50:325-32.  Back to cited text no. 23
    
24.
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. 24
    
25.
Simonelli M, Dipasquale A, Orzan F, Lorenzi E, Persico P, Navarria P, et al. Cerebrospinal fluid tumor DNA for liquid biopsy in glioma patients' management: Close to the clinic? Crit Rev Oncol Hematol 2020;146:102879.  Back to cited text no. 25
    
26.
Pan C, Diplas BH, Chen X, Wu Y, Xiao X, Jiang L, 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. 26
    
27.
Liang J, Zhao W, Lu C, Liu D, Li P, Ye X, et al. Next-generation sequencing analysis of ctDNA for the detection of glioma and metastatic brain tumors in adults. Front Neurol 2020;11:544.  Back to cited text no. 27
    
28.
Szopa W, Burley TA, Kramer-Marek G, Kaspera W. Diagnostic and therapeutic biomarkers in glioblastoma: Current status and future perspectives. Biomed Res Int 2017;2017:8013575.  Back to cited text no. 28
    
29.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66.  Back to cited text no. 29
    
30.
Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, et al. Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: The NOA-08 randomised, phase 3 trial. Lancet Oncol 2012;13:707-15.  Back to cited text no. 30
    
31.
Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, et al.; Nordic Clinical Brain Tumour Study Group (NCBTSG). Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: The Nordic randomised, phase 3 trial. Lancet Oncol 2012;13:916-26.  Back to cited text no. 31
    
32.
Brandes AA, Franceschi E, Tosoni A, Bartolini S, Bacci A, Agati R, et al. O (6)-methylguanine DNA-methyltransferase methylation status can change between first surgery for newly diagnosed glioblastoma and second surgery for recurrence: Clinical implications. Neuro Oncol 2010;12:283-8.  Back to cited text no. 32
    
33.
Balaña C, Ramirez JL, Taron M, Roussos Y, Ariza A, Ballester R, et al. O6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1,3-bis (2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme. Clin Cancer Res 2003;9:1461-8.  Back to cited text no. 33
    
34.
Weaver KD, Grossman SA, Herman JG. Methylated tumor-specific DNA as a plasma biomarker in patients with glioma. Cancer Invest 2006;24:35-40.  Back to cited text no. 34
    
35.
Majchrzak-Celińska A, Paluszczak J, Kleszcz R, Magiera M, Barciszewska AM, Nowak S, et al. Detection of MGMT, RASSF1A, p15INK4B, and p14ARF promoter methylation in circulating tumor-derived DNA of central nervous system cancer patients. J Appl Genet 2013;54:335-44.  Back to cited text no. 35
    
36.
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. 36
    
37.
Zachariah MA, Oliveira-Costa JP, Carter BS, Stott SL, Nahed BV. Blood-based biomarkers for the diagnosis and monitoring of gliomas. Neuro Oncol 2018;20:1155-61.  Back to cited text no. 37
    
38.
Liu BL, Cheng JX, Zhang W, Zhang X, Wang R, Lin H, et al. Quantitative detection of multiple gene promoter hypermethylation in tumor tissue, serum, and cerebrospinal fluid predicts prognosis of malignant gliomas. Neuro Oncol 2010;12:540-8.  Back to cited text no. 38
    
39.
Sun ZL, Chan AK, Chen LC, Tang C, Zhang ZY, Ding XJ, et al. TERT promoter mutated WHO grades II and III gliomas are located preferentially in the frontal lobe and avoid the midline. Int J Clin Exp Pathol 2015;8:11485-94.  Back to cited text no. 39
    
40.
Labussière M, Boisselier B, Mokhtari K, Di Stefano AL, Rahimian A, Rossetto M, et al. Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes. Neurology 2014;83:1200-6.  Back to cited text no. 40
    
41.
Kim HS, Kwon MJ, Song JH, Kim ES, Kim HY, Min KW. Clinical implications of TERT promoter mutation on IDH mutation and MGMT promoter methylation in diffuse gliomas. Pathol Res Pract 2018;214:881-8.  Back to cited text no. 41
    
42.
Pekmezci M, Rice T, Molinaro AM, Walsh KM, Decker PA, Hansen H, et al. Adult infiltrating gliomas with WHO 2016 integrated diagnosis: Additional prognostic roles of ATRX and TERT. Acta Neuropathol 2017;133:1001-16.  Back to cited text no. 42
    
43.
Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB, et al. cIMPACT-NOW update 3: Recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. Acta Neuropathol 2018;136:805-10.  Back to cited text no. 43
    
44.
Baerlocher GM, Oppliger Leibundgut E, Ottmann OG, Spitzer G, Odenike O, McDevitt MA, et al. Telomerase inhibitor imetelstat in patients with essential thrombocythemia. N Engl J Med 2015;373:920-8.  Back to cited text no. 44
    
45.
Marian CO, Cho SK, McEllin BM, Maher EA, Hatanpaa KJ, Madden CJ, et al. The telomerase antagonist, imetelstat, efficiently targets glioblastoma tumor-initiating cells leading to decreased proliferation and tumor growth. Clin Cancer Res 2010;16:154-63.  Back to cited text no. 45
    
46.
Salloum R, Hummel TR, Kumar SS, Dorris K, Li S, Lin T, et al. A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: A pediatric brain tumor consortium study. J Neurooncol 2016;129:443-51.  Back to cited text no. 46
    
47.
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. 47
    
48.
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;8:179.  Back to cited text no. 48
    
49.
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. 49
    
50.
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. 50
    
51.
Kuan CT, Wikstrand CJ, Bigner DD. EGF mutant receptor vIII as a molecular target in cancer therapy. Endocr Relat Cancer 2001;8:83-96.  Back to cited text no. 51
    
52.
Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res 2003;63:6962-70.  Back to cited text no. 52
    
53.
Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, et al. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 2001;93:1246-56.  Back to cited text no. 53
    
54.
Hobbs J, Nikiforova MN, Fardo DW, Bortoluzzi S, Cieply K, Hamilton RL, et al. Paradoxical relationship between the degree of EGFR amplification and outcome in glioblastomas. Am J Surg Pathol 2012;36:1186-93.  Back to cited text no. 54
    
55.
Montano N, Cenci T, Martini M, D'Alessandris QG, Pelacchi F, Ricci-Vitiani L, et al. Expression of EGFRvIII in glioblastoma: Prognostic significance revisited. Neoplasia 2011;13:1113-21.  Back to cited text no. 55
    
56.
Heimberger AB, Hlatky R, Suki D, Yang D, Weinberg J, Gilbert M, et al. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res 2005;11:1462-6.  Back to cited text no. 56
    
57.
Figueroa JM, Skog J, Akers J, Li H, Komotar R, Jensen R, et al. Detection of wild-type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients. Neuro Oncol 2017;19:1494-502.  Back to cited text no. 57
    
58.
Manda SV, Kataria Y, Tatireddy BR, Ramakrishnan B, Ratnam BG, Lath R, et al. Exosomes as a biomarker platform for detecting epidermal growth factor receptor-positive high-grade gliomas. J Neurosurg 2018;128:1091-101.  Back to cited text no. 58
    
59.
Kristensen BW, Priesterbach-Ackley LP, Petersen JK, Wesseling P. Molecular pathology of tumors of the central nervous system. Ann Oncol 2019;30:1265-78.  Back to cited text no. 59
    
60.
Benitez JA, Ma J, D'Antonio M, Boyer A, Camargo MF, Zanca C, et al. PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3. Nat Commun 2017;8:15223.  Back to cited text no. 60
    
61.
Yang JM, Schiapparelli P, Nguyen HN, Igarashi A, Zhang Q, Abbadi S, et al. Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization. Oncogene 2017;36:3673-85.  Back to cited text no. 61
    
62.
Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012;482:226-31.  Back to cited text no. 62
    
63.
Haase S, Nuñez FM, Gauss JC, Thompson S, Brumley E, Lowenstein P, et al. Hemispherical pediatric high-grade glioma: Molecular basis and therapeutic opportunities. Int J Mol Sci 2020;21:9654.  Back to cited text no. 63
    
64.
Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 2012;44:251-3.  Back to cited text no. 64
    
65.
Manjunath N, Jha P, Singh J, Raheja A, Kaur K, Suri A, et al. Clinico-pathological and molecular characterization of diffuse midline gliomas: Is there a prognostic significance? Neurol Sci 2021;42:925-34.  Back to cited text no. 65
    
66.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 world health organization classification of tumors of the central nervous system: A summary. Acta Neuropathol 2016;131:803-20.  Back to cited text no. 66
    
67.
Hargrave D, Chuang N, Bouffet E. Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma. J Neurooncol 2008;86:313-9.  Back to cited text no. 67
    
68.
Laprie A, Pirzkall A, Haas-Kogan DA, Cha S, Banerjee A, Le TP, et al. Longitudinal multivoxel MR spectroscopy study of pediatric diffuse brainstem gliomas treated with radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:20-31.  Back to cited text no. 68
    
69.
Riley GT, Armitage PA, Batty R, Griffiths PD, Lee V, McMullan J, et al. Diffuse intrinsic pontine glioma: Is MRI surveillance improved by region of interest volumetry? Pediatr Radiol 2015;45:203-10.  Back to cited text no. 69
    
70.
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. 70
    
71.
Li D, Bonner ER, Wierzbicki K, Panditharatna E, Huang T, Lulla R, et al. Standardization of the liquid biopsy for pediatric diffuse midline glioma using ddPCR. Sci Rep 2021;11:5098.  Back to cited text no. 71
    
72.
Smoll NR, Drummond KJ. The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children. J Clin Neurosci 2012;19:1541-4.  Back to cited text no. 72
    
73.
Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: The current consensus. Acta Neuropathol 2012;123:465-72.  Back to cited text no. 73
    
74.
Northcott PA, Buchhalter I, Morrissy AS, Hovestadt V, Weischenfeldt J, Ehrenberger T, et al. The whole-genome landscape of medulloblastoma subtypes. Nature 2017;547:311-7.  Back to cited text no. 74
    
75.
Cavalli FM, Remke M, Rampasek L, Peacock J, Shih DJ, Luu B, et al. Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell 2017;31:737-54.e6.  Back to cited text no. 75
    
76.
Schwalbe EC, Lindsey JC, Nakjang S, Crosier S, Smith AJ, Hicks D, et al. Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: A cohort study. Lancet Oncol 2017;18:958-71.  Back to cited text no. 76
    
77.
Hovestadt V, Ayrault O, Swartling FJ, Robinson GW, Pfister SM, Northcott PA. Medulloblastomics revisited: Biological and clinical insights from thousands of patients. Nat Rev Cancer 2020;20:42-56.  Back to cited text no. 77
    
78.
Escudero L, Llort A, Arias A, Diaz-Navarro A, Martínez-Ricarte F, Rubio-Perez C, et al. Circulating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma. Nat Commun 2020;11:5376.  Back to cited text no. 78
    
79.
Hovestadt V, Jones DT, Picelli S, Wang W, Kool M, Northcott PA, et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 2014;510:537-41.  Back to cited text no. 79
    
80.
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. 80
    
81.
Pan W, Gu W, Nagpal S, Gephart MH, Quake SR. Brain tumor mutations detected in cerebral spinal fluid. Clin Chem 2015;61:514-22.  Back to cited text no. 81
    
82.
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. Proc Natl Acad Sci U S A 2015;112:9704-9.  Back to cited text no. 82
    
83.
Connolly ID, Li Y, Pan W, Johnson E, You L, Vogel H, et al. A pilot study on the use of cerebrospinal fluid cell-free DNA in intramedullary spinal ependymoma. J Neurooncol 2017;135:29-36.  Back to cited text no. 83
    
84.
Fontanilles M, Marguet F, Bohers É, Viailly PJ, Dubois S, Bertrand P, et al. Non-invasive detection of somatic mutations using next-generation sequencing in primary central nervous system lymphoma. Oncotarget 2017;8:48157-68.  Back to cited text no. 84
    
85.
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. 85
    
86.
Bobillo S, Crespo M, Escudero L, Mayor R, Raheja P, Carpio C, et al. Cell free circulating tumor DNA in cerebrospinal fluid detects and monitors central nervous system involvement of B-cell lymphomas. Haematologica 2021;106:513-21.  Back to cited text no. 86
    
87.
Grommes C, Tang SS, Wolfe J, Kaley TJ, Daras M, Pentsova EI, et al. Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Blood 2019;133:436-45.  Back to cited text no. 87
    
88.
Hiemcke-Jiwa LS, Minnema MC, Radersma-van Loon JH, Jiwa NM, de Boer M, Leguit RJ, et al. The use of droplet digital PCR in liquid biopsies: A highly sensitive technique for MYD88 p.(L265P) detection in cerebrospinal fluid. Hematol Oncol 2018;36:429-35.  Back to cited text no. 88
    
89.
Hiemcke-Jiwa LS, Leguit RJ, Snijders TJ, Bromberg JEC, Nierkens S, Jiwa NM, et al. MYD88 p.(L265P) detection on cell-free DNA in liquid biopsies of patients with primary central nervous system lymphoma. Br J Haematol 2019;185:974-7.  Back to cited text no. 89
    
90.
Hickmann AK, Frick M, Hadaschik D, Battke F, Bittl M, Ganslandt O, et al. Molecular tumor analysis and liquid biopsy: A feasibility investigation analyzing circulating tumor DNA in patients with central nervous system lymphomas. BMC Cancer 2019;19:192.  Back to cited text no. 90
    
91.
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. 91
    
92.
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;565:654-65.  Back to cited text no. 92
    



 
 
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Diffuse Gliomas
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