Liquid Biopsy for Solid Ophthalmic Malignancies: An Updated Review and Perspectives
Abstract
Simple Summary
Abstract
1. Introduction
2. Liquid Biopsy in Uveal Melanoma (UM)
2.1. Molecular Characteristics of UM
2.2. CTCs
2.2.1. CTC Isolation and Identification
2.2.2. Main Clinical Findings
2.3. Ct-DNA and ct-RNA
2.3.1. Ct-DNA and ct-RNA Detection
2.3.2. Main Clinical Findings
2.4. Non-Coding RNAs
2.4.1. Non-Coding RNAs Detection
2.4.2. Main Clinical Findings
2.5. Tumor-Related Exosomes (TREs)
2.5.1. TRE Detection
2.5.2. Main Clinical Findings
2.6. Tumor-Educated Platelets (TEPs)
2.7. Future Perspectives: Towards a Better UM Understanding?
2.8. Limitations
2.9. Conclusion
3. Retinoblastoma (RB)
4. LB in Conjunctival Malignancies
5. LB in Choroidal Metastases
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Antibody Marker | Molecular Marker |
---|---|
Melan-A | Tyrosinase |
HMW-MAA | GNAQ, GNA11 |
GP 100 | BAP 1 |
Authors | Study Population | Number of Patients | CTC Isolation Method and Device | CTC Identification | Mean CTC (Range) | Main Findings | Follow-Up: Months (Range) |
---|---|---|---|---|---|---|---|
Anand et al. [29] | Primary and metastatic UM | 39 patients 20 primary UM 19 metastatic UM | Immunomagnetism Cellsearch | Cellsearch protocol: DAPI+ HMW-MAA+ CD146+ CD45- CD34- | 5.9 (1–38) | At initial sampling: CTC detected in 14 out of 39 (36%) patients. CTC detected in 6/20 (30%) primary UM and 8/19 (42%) metastatic UM During the follow-up period: CTC detected in 21/39 (54%) of patients CTC were more likely detected in Class 2 UM (83%) | 16.4 |
Tura et al. [30] | Primary UM | 44 UM patients | Immuno-FISH isolation | NKIC3 and MCSP antibodies | Median: 2.4 (0–10.2) Median CTC in Monosomy 3 patients: 3.4 (0.7–10.2) Median CTC without Monosomy 3: 1.2 (0.3–8.4) | CTC detected in 40/444 (91%) patients Monosomy 3 detected in 23/40 (58%) patients Monosomy 3 on CTC associated with a higher TNM stage (T3) | 48 |
Bande et al. [31] | Primary UM Uveal naevi | 12 patients 8 primary UM 4 uveal naevi | Immunomagnetism CellSearch | Cellsearch protocol: DAPI+ HMW-MAA+ CD146+ CD45- CD34- | UM: 1 (0–3) | CTC detected in 50% of UM patients and 0% in uveal naevi No relationship between CTC detection and the UM clinical-pathological features | 25 (16–27) |
Terai et al. [32] | Metastatic UM | 17 patients 10 hepatic metastases 7 extra hepatic metastases | Immunomagnetism CellSearch | Cellsearch protocol: DAPI+ HMW-MAA+ CD146+ CD45- CD34- | Arterial: median: 5 (1–168) Venous: median: 1 (0–5) | No morphological difference between CTC collected through the arterial and venous route Arterial blood: CTC detection in 100% of cases Venous blood: CTC detection in 52.9% of cases No correlation between CTC number and number and size of metastases | None |
Tura et al. [33] | Primary UM | 31 patients | Immunomagnetism Immunobeads | 2 antibodies: NKI/C3, NKI/beteb | Median: 3.5 (0–10.2) | CTC detected in 29/31 (93.6%) of patients No correlation between the CTC count and clinical parameters | None |
Mazzini et al. [34] | Primary UM Metastatic UM Uveal nevi | 31 UM 10 uveal nevi | Isolation by size ISET | Antibodies anti S100, anti MART-1 and anti-tyrosinase | Median 8 (2–50) | CTC detected in 17/31 (55%) of UM patients. No CTC detected in uveal nevi patients No correlation between clinical and biological parameters and CTC positivity Detection of >10 CTC associated with a larger basal diameter, tumor height, disease free survival, and OS | 24–60 |
Bidard et al. [35] | Metastatic UM | 40 patients | For CTC detection: Immunomagentism Cellsearch For Ct-DNA detection: BiPAP technique with 3 mutations screening: GNAQ c.626A > T, GNAQ c.626A > C and GNA11 c.626A > T | Cellsearch protocol: DAPI+ HMW-MAA+ CD146+ CD45- CD34- | 0 CTC: 70% ≥ 1 CTC: 30% 1 CTC: 10% 3 CTC: 15% 12 CTC: 2.5% 20 CTC: 2.5% DNA quantity: Median: 4.1 ng/mL (0.5–512) | Liver miliary associated with higher ct-DNA levels and CTC counts Correlation between CTC, ct-DNA, and tumor volume assessed by liver MRI Univariate analysis: CTC and ct-DNA positivity associated with PFS and OS Multivariate analysis: Only ct-DNA was associated with PFS and OS | 8 (median) |
Pinzani et al. [36] | Primary UM Healthy Controls | 41 primary UM 16 controls | mRNA detected by RT-PCR (41 patients) CTC: Isolation by size using ISET device (16 patients) Blood samples repeated every 6 months | CTC morphology: cell size > 16-micron, nucleocytoplasmic ratio > 50%, irregular nuclear shape, hyperchromatic nucleus, and basophilic cytoplasm | PCR: median: 0.8 cell equivalent /mL of blood (0.1–14.4) ISET: 5.8, 2.33, 2.00, 1.25, and 0.75 CTC/ml | RT-PCR positivity in 20/41 (49%) of patients among at least one of the blood samples PCR positivity associated with decreased PFS and OS CTC detected in 5/16 (31%) patients Tyrosinase level correlated with CTC detection | 55 |
Suesskind et al. [37] | Primary UM | 81 primary UM 94 samples before /after treatment | Immunomagnetism MACS | MCSP antibody | Preoperative median CTC count: 1 (1–8) Post-treatment: median CTC count: 7.5 (1–26) | CTC count before and after treatment (enucleation =7, radiotherapy stereotaxic =49, endoresection =19, brachytherapy =15, thermotherapy = 4) Before treatment: CTC detected in 13/94 (14%) of patients After treatment: CTC detected in 9/94 (10%) of patients No significant difference in terms of the CTC count before and after treatment No relationship between the CTC positivity and patient characteristics and metastatic status | 16 (median) |
Eide et al. [38] | Primary UM | 328 patients | Immunomagnetism | Several anti-melanoma antibodies (9.2.27 antimelanoma-associated antibody, IgG1 Ep-1 antibody, 376.96 antibody) | Median cells number: 50 (1–500) | CTC detected in 4/328 (1,6%) patients Tumor cells detected in 98/328 (29.9%) patients in bone marrow No relationship between bone marrow tumor detection and further metastatic spread | 60 |
Ulmer et al. [39] | Primary UM Healthy controls | 52 primary UM before treatment 20 healthy controls | Immunomagnetism MACS | MCSP antibody | Median: 2.5 (1–5) for 50 ml | CTC detected in 10/52 (19%) of patients No CTC detected in controls CTC positivity associated with ciliary body invasion, advanced local tumor stage, and anterior tumor localization Multivariate analysis: Only ciliary body involvement associated with CTC positivity | None |
Authors | Study Population | Number of Patients | Ct-DNA/ct-RNA Detection | Main Findings | Follow-Up: Months (Range) |
---|---|---|---|---|---|
Charitoudis et al. [46] | Primary UM undergoing surgery | 202 patients | RT-PCR screening tyrosinase and MELAN-A/MART-1 | RT-PCR tyrosinase positive in 2/184 (1.1%) patients before and 4/180 (2.2%) patients after surgery RT-PCR MELAN-A/MART-1 positive in 20/184 (10.9%) before and in 25/180 (13.9%) patients after surgery RT-PCR results on MELAN-A/MART-1 and Tyrosinase levels were not affected by surgical manipulation | 24 |
Metz et al. [47] | Primary and metastatic UM | 28 patients | PCR screening GNAQ Q209 (298 bp), GNAQ R183 (212 bp), GNA11 Q209 (150 bp), and GNA11 R183 (249 bp) | Oncogenic GNAQ/GNA11 mutations identified in ct-DNA of 9 out of 22 (41%) metastatic patients. Ct-DNA correlated with the metastatic status ct-DNA detected in younger patients with larger metastases | None |
Schuster et al. [48] | Metastatic UM | 68 patients | RT-PCR screening tyrosinase and MELAN-A/MART 1 | RT-PCR positive in 43/68 (63%) patients 31 patients positive for tyrosinase 40 patients positive for MELAN-A /MART 1 28 patients positive for both RT-PCR positivity associated with poorer PFS and OS | 10 (median) |
Schuster et al. [49] | Primary UM | 110 patients | RT-PCR screening tyrosinase, MELAN-A/ MART1 | RT-PCR positive in 11/110 (10%) patients (5 tyrosinase, 5 MALAN-A/MART1, 1 both) No correlation between RT-PCR positivity and clinical features Univariate analysis: The relationship between RT-PCR positivity and time to progression and OS RT-PCR positivity indicated an increased risk of metastasis and disease-specific mortality | 22 (median) |
Callejo et al. [50] | Primary UM | 30 patients | RT-PCR screening tyrosinase, Melan-A | RT-PCR positive in 29/30 (97%) patients (119 visits, 1360 samples, 2720 PCR performed) No correlation between RT-PCR positivity, tumor size and treatment | NR |
Boldin et al. [51] | Primary UM | 41 patients | RT-PCR screening tyrosinase | RT-PCR positive in 16/41 (39%) patients at baseline 11/16 (69%) patients initially positive were negative after treatment RT-PCR positivity associated with decreased 5-year OS RT-PCR positivity not correlated with tumor size and histology | 60–66 |
Keilholz et al. [52] | Primary and metastatic UM | 61 patients 21 primary UM 40 metastatic UM | RT-PCR screening tyrosinase, MELAN-A/MART-1 and GP100 | Primary UM: tyrosinase detected in 3 (12.5%) patients, MELAN/MART detected in 1 (4%) patient and GP100 detected in 1 (4%) patient. Metastatic UM: Tyrosinase detected in 24 (60%) patients, Melan/MART 31 (77%) patients and GP100 in 4/26 (15%) patients GP100 positive in 4/40 (10%) samples. Accuracy detection rates: Tyrosinase > Melan > GP100 | 6 |
LB Feature | Advantages | Disadvantages |
---|---|---|
CTC | ● Allows a better understanding of the metastatic process by screening genetical mutations and surface biomarkers ● Allows laboratory cell culture and further in vivo investigations | ● Lack of consensus concerning pre- and post-analytic processes ● May be less reliable than ct-DNA, according to Bidard et al. |
Ct-DNA | ● More reliable and standardized techniques compared to CTC ● More stable than ct-RNA | ● Less instructive than CTC in understanding the underlying tumorigenesis ● GNAQ and GNA11 mutations are not found in all UM |
Ct-RNA | ● Detection by reliable techniques (RT-PCR) | ● Instability (degradation by RNAase) Low abundance ● Half-life very low |
miRNA | ● Longer half-life, especially when encapsulated ● More stable compared to ct-DNA and ct-RNA ● Detected by reliable techniques (RT-PCR) | ● Lack of consensus regarding pre- and post-analytic processes ● Conflicting results regarding the role of certain mi-RNAs |
TRE | ● Stable ● Long half-life ● Possibility to investigate mi-RNA, DNA, RNA, as well as surface markers | ● Lack of consensus regarding exosome definition (different definitions based on the size to distinguish exosomes from other small extracellular vesicles) ● Lack of available studies ● Lack of process standardization |
TEP | ● Promising preliminary results in other solid malignancies ● TEPs are easily obtained and processed ● Available in large amounts | ● Lack of studies into UM |
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Martel, A.; Baillif, S.; Nahon-esteve, S.; Gastaud, L.; Bertolotto, C.; Roméo, B.; Mograbi, B.; Lassalle, S.; Hofman, P. Liquid Biopsy for Solid Ophthalmic Malignancies: An Updated Review and Perspectives. Cancers 2020, 12, 3284. https://doi.org/10.3390/cancers12113284
Martel A, Baillif S, Nahon-esteve S, Gastaud L, Bertolotto C, Roméo B, Mograbi B, Lassalle S, Hofman P. Liquid Biopsy for Solid Ophthalmic Malignancies: An Updated Review and Perspectives. Cancers. 2020; 12(11):3284. https://doi.org/10.3390/cancers12113284
Chicago/Turabian StyleMartel, Arnaud, Stephanie Baillif, Sacha Nahon-esteve, Lauris Gastaud, Corine Bertolotto, Barnabé Roméo, Baharia Mograbi, Sandra Lassalle, and Paul Hofman. 2020. "Liquid Biopsy for Solid Ophthalmic Malignancies: An Updated Review and Perspectives" Cancers 12, no. 11: 3284. https://doi.org/10.3390/cancers12113284
APA StyleMartel, A., Baillif, S., Nahon-esteve, S., Gastaud, L., Bertolotto, C., Roméo, B., Mograbi, B., Lassalle, S., & Hofman, P. (2020). Liquid Biopsy for Solid Ophthalmic Malignancies: An Updated Review and Perspectives. Cancers, 12(11), 3284. https://doi.org/10.3390/cancers12113284