Liquid biopsies for the diagnosis and surveillance of primary pediatric central nervous system tumors: a review for practicing neurosurgeons

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>Primary brain tumors are the most common cause of cancer-related deaths in children and pose difficult questions for the treating physician regarding issues such as the risk/benefit of performing a biopsy, the accuracy of monitoring methods, and the availability of prognostic indicators. It has been recently shown that tumor-specific DNA and proteins can be successfully isolated in liquid biopsies, and it may be possible to exploit this potential as a particularly useful tool for the clinician in addressing these issues.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>A review of the current literature was conducted by searching PubMed and Scopus. MeSH terms for the search included “liquid biopsy,” “brain,” “tumor,” and “pediatrics” in all fields. Articles were reviewed to identify the type of brain tumor involved, the method of tumor DNA/protein analysis, and the potential clinical utility. All articles involving primary studies of pediatric brain tumors were included, but reviews were excluded.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>The successful isolation of circulating tumor DNA (ctDNA), extracellular vesicles, and tumor-specific proteins from liquid biopsies has been consistently demonstrated. This most commonly occurs through CSF analysis, but it has also been successfully demonstrated using plasma and urine samples. Tumor-related gene mutations and alterations in protein expression are identifiable and, in some cases, have been correlated to specific neoplasms. The quantity of ctDNA isolated also appears to have a direct relationship with tumor progression and response to treatment.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>The use of liquid biopsies for the diagnosis and monitoring of primary pediatric brain tumors is a foreseeable possibility, as the requisite developmental steps have largely been demonstrated. Increasingly advanced molecular methods are being developed to improve the identification of tumor subtypes and tumor grades, and they may offer a method for monitoring treatment response. These minimally invasive markers will likely be used in the clinical treatment of pediatric brain tumors in the future.</jats:p></jats:sec>

Standardization of the liquid biopsy for pediatric diffuse midline glioma using ddPCR

“…We previously reported H3F3A c.83 A > T (H3.3K27M) mutation detection in circulating tumor DNA (ctDNA) in CSF and plasma of children with DMG, and developed a digital droplet PCR (ddPCR) approach to detect and monitor H3.3K27M mutation in ctDNA from the DMG liquid biome 17 – 19 . Our work, and mounting evidence in the literature, demonstrate that liquid biopsy is a viable tool for clinicians to diagnose and monitor pediatric CNS tumors 20 . Clinical implementation of this approach requires exquisite test reliability, sensitivity and specificity.…”

Liquid Biomarkers for Pediatric Brain Tumors: Biological Features, Advantages and Perspectives

“…In addition, the availability of targeted therapy has increased the need for longitudinal monitoring of molecular changes within tumors in order to precisely guide anti-cancer treatment. Hence, there is a compelling need for the indirect assessment of tumors at certain time points via less-invasive tumor markers which can be gained from body fluids of the patient [ 6 , 7 ]. The most proximal source for liquid biopsy for pediatric brain tumors is the cerebrospinal fluid (CSF) followed by peripheral blood including its components serum/plasma and urine [ 8 ] ( Figure 1 ).…”

“…Multiple different molecular structures have been identified in the liquids of pediatric brain tumor patients and raised the interest of the scientific field. These biomarkers include circulating tumor cells (CTCs) [ 18 , 19 ], circulating tumor DNA (ctDNA) [ 7 , 18 , 19 ], cell-free DNA (cfDNA) [ 6 , 18 , 19 , 20 , 21 ], circulating proteins [ 6 , 8 , 19 , 20 ], extracellular vesicles and exosomes [ 5 , 18 , 22 , 23 , 24 , 25 , 26 ], micro-RNAs (miRNAs) [ 5 , 19 , 27 , 28 , 29 , 30 , 31 , 32 ], long non-coding RNA (lncRNA) [ 33 ] and other genetic alterations [ 28 , 34 , 35 , 36 , 37 , 38 ]. Detection of these biomolecules may offer advantages compared to surgical interventions.…”

Cross-platform Profiling of ctDNA&nbsp;Using ddPCR: Standardization of the Liquid Biopsy for Pediatric Diffuse Midline Glioma

“…We previously reported H3F3A c.83 A->T (H3.3K27M) mutation detection in circulating tumor DNA (ctDNA) in CSF and plasma from children with DMG, and developed a digital droplet PCR (ddPCR) approach to detect and monitor H3K27M in ctDNA from the DMG liquid biome (17)(18)(19). This work, and mounting evidence in the literature, demonstrate liquid biopsy as a viable tool for clinicians to diagnose and monitor pediatric CNS tumors (20). Clinical implementation of this approach requires exquisite test reliability, sensitivity and speci city, but differences in ddPCR instruments and protocols impede broad clinical application of this technique.…”