The Role of Liquid Biopsies in Detecting Molecular Tumor Biomarkers in Brain Cancer Patients
Abstract
1. Introduction
2. Molecular Biomarkers in Brain Cancer
2.1. Glial Fibrillary Acidic Protein (GFAP)
2.2. Methylguanine-DNA Methyltransferase Promoter Methylation (MGMT)
2.3. Isocitrate Dehydrogenase Mutations (IDH1/2)
2.4. Epidermal Growth Factor Receptor (EGFR)
2.5. Telomerase Promoter Mutations (TERT)
2.6. Loss of Heterozygosity
3. Liquid Biopsies
3.1. Circulating Tumor Cells (CTCs)
3.2. Circulating Tumor Nucleic Acids (ctNAs)
3.3. Cerebro-Spinal Fluid
3.4. Exosomes
4. Conclusions
Funding
Conflicts of Interest
References
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Marker | Clinical Utility in Brain Cancer | Detected in Brain Cancer Circulating Tumor Cells (CTCs) | Detected in Brain Cancer ctNAs | Detected in CTCs or ctNAs # |
---|---|---|---|---|
GFAP | Yes [10] | Yes [11] | No | No |
MGMT * | Yes [12] | No | Yes + [13] | Yes, colorectal cancer [14] |
IDH1 | Yes [15] | No | Yes + [16] | Yes, leukaemia [17] |
EGFR ** | Emerging [18] | No | Yes + [19] | Yes, lung cancer [20,21] |
hTERT | Emerging [22] | Yes [7] | Yes + [23] | Yes, Urothelial cancer [24], Metastatic breast cancer [25] |
LOH chr10 | Yes [26] | No | Yes + [8] | Yes, Ovarian cancer [27] |
CTC isolation/ID Method (Reference) | Patient No. | CTC Counts # | Efficiency * | Biomarker Tested | Clinical Utility | Limitations |
---|---|---|---|---|---|---|
Lentiviral telomerase reverse transcriptase (TERT)-promoter based detection [7] | 11 | 8.8 (pre-RT) | pre-RT: 72% (8/11) post RT: 8% (1/11) | Epidermal growth factor receptor (EGFR) amplification | Prognostic marker (increased CTC count with recurrence) | Small cohort size, requires viral transduction limited to viable cells, may affect biomarker detection |
Gradient PBMCs/CTC enrichment, immunocytostainig for glial fibrillary acidic protein (GFAP) [11] | 141 | 0.1–2.2 | 20.6% (29/141) | EGFR amplification | No correlation with OS | GFAP heterogeneous in GBM, use as sole ID marker may under-estimate CTC counts |
CTC-ichip leucocytes depletion, CTC ID with probing for SOX2, Tubulin b-3, EGFR, A2B5 and c-MET [72] | 33 | 11.8 (progressive disease) 2.1 (stable disease) | 39% (13/33) | N/A | Prognostic marker (progressive disease with greater frequency of CTCs) | Small cohort size |
FISH CTC detection (chromosome 8 polyploidy) and exclusion of CD45+ cells [69] | 31 | 0.13–1.33 | 71% (24/31) | N/A | CTC count decreases post adjuvant therapy, CTCs may help distinguish radio-necrosis from true tumor progression | Small cohort size |
Parsortix platform for size based CTC capture, CTC ID testing by EGFR, Ki67, EB1 probing [73] | 13 | 0.3, 1 patient: CTC clusters | 53.8% (7/13) | NGS: APC, XPO1, TFRC, JAK2, BRCA2, ERBB4 and ALK | N/A | Small cohort size |
VAR2CSA malaria protein based targeted immunomagnetic isolation [74] | 5 (GBM) | 3.5~ | 80% (4/5) | NGS: IDHI, RB1, ALK, LOH 1p/19q, MGMT | N/A | Small cohort size, use of VAR2CSA for both isolation and ID may reduce specificity of CTC detection |
MCAM, MCSP targeted immunomagnetic isolation, GFAP and GLAST probing [75] | 13 (15 samples) | 1.5 | 60% (9/15) | N/A | No correlation of CTC counts with PFS/OS | Small cohort size |
ctDNA Source (Reference) | Patients No | Biomarker Tested | Percentage Detection # | Relevance to Disease |
---|---|---|---|---|
Plasma ctDNA, CSF ctDNA [81] | 12 | NGS: EGFR, PTEN, ESR1, IDH1, ERBB2, FGFR2 | “higher” sensitivity of mutation detection from CSF ctDNA | Nd |
Plasma ctDNA, CSF ctDNA [82] | 85 | NGS: TERT, TP53, IDH1, EGFR, and EGFRvIII | 49.4% vs. 15.7% CSF vs. plasma ctDNA | Prognostic: shorter survival of CSF ctDNA positive patients |
Plasma ctDNA, CSF ctDNA [23] | 38 | pTERT mutation | 92.1% vs. 7.9% CSF vs. plasma ctDNA | pTERT mutation potential poor survival predictor |
Plasma ctDNA, CSF ctDNA * [83] | 21 | NGS: EGFR, KIT, PIK3CA, TP53, SMAD4, ATM, SMARCB1, PTEN | 95.2% vs. 66.7% CSF vs. plasma ctDNA | Nd |
Plasma ctDNA, CSF ctDNA [84] | 7 | NGS: NF2, AKT, BRAF, NRAS, EGFR | CSF ctDNA detection “significantly higher” with low systemic disease burden | Nd |
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Sareen, H.; Garrett, C.; Lynch, D.; Powter, B.; Brungs, D.; Cooper, A.; Po, J.; Koh, E.-S.; Vessey, J.Y.; McKechnie, S.; et al. The Role of Liquid Biopsies in Detecting Molecular Tumor Biomarkers in Brain Cancer Patients. Cancers 2020, 12, 1831. https://doi.org/10.3390/cancers12071831
Sareen H, Garrett C, Lynch D, Powter B, Brungs D, Cooper A, Po J, Koh E-S, Vessey JY, McKechnie S, et al. The Role of Liquid Biopsies in Detecting Molecular Tumor Biomarkers in Brain Cancer Patients. Cancers. 2020; 12(7):1831. https://doi.org/10.3390/cancers12071831
Chicago/Turabian StyleSareen, Heena, Celine Garrett, David Lynch, Branka Powter, Daniel Brungs, Adam Cooper, Joseph Po, Eng-Siew Koh, Joey Yusof Vessey, Simon McKechnie, and et al. 2020. "The Role of Liquid Biopsies in Detecting Molecular Tumor Biomarkers in Brain Cancer Patients" Cancers 12, no. 7: 1831. https://doi.org/10.3390/cancers12071831
APA StyleSareen, H., Garrett, C., Lynch, D., Powter, B., Brungs, D., Cooper, A., Po, J., Koh, E.-S., Vessey, J. Y., McKechnie, S., Bazina, R., Sheridan, M., Gelder, J. v., Darwish, B., Jaeger, M., Roberts, T. L., De Souza, P., & Becker, T. M. (2020). The Role of Liquid Biopsies in Detecting Molecular Tumor Biomarkers in Brain Cancer Patients. Cancers, 12(7), 1831. https://doi.org/10.3390/cancers12071831