MMP-1, UCH-L1, and 20S Proteasome as Potential Biomarkers Supporting the Diagnosis of Brain Glioma
Abstract
:1. Introduction
2. Materials and Methods
2.1. Reagents
2.2. Biological Material
2.3. Procedure for Quantifying MMP-1, UCH-L1, and Proteasome—SPRi Measurements
2.4. IDH 1/2 Mutation, p53 Gene Mutation, and EGFR Expression
3. Results
3.1. Statistical Analysis
3.2. ROC Analysis
3.3. Impact of IDH Status on Biomarkers
4. Discussion and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Control Group/Tumor Grade | |||||||
---|---|---|---|---|---|---|---|
Variable | K n = 48 | G1 n = 3 | G2 n = 10 | G3 n = 7 | G4 n = 37 | Age Difference Between K and G1–G4 A | |
Age (years) | range | 39–66 | 29–43 | 30–57 | 38–72 | 33–77 | No statistically significant difference (p > 0.05) |
median | 61 | 39 | 43.5 | 45 | 60 | ||
Gender | male | 27 | 1 | 5 | 3 | 26 | |
female | 21 | 2 | 5 | 4 | 11 | ||
Tumor size (cm2) | <15 | 2 | 2 | 3 | 10 | ||
>15 | 1 | 2 | 1 | 10 | |||
The presence of other neo-plasms in the immediate family | yes | 0 | 6 | 3 | 17 | ||
no | 3 | 4 | 4 | 20 | |||
Concomitant non-cancerous diseases | yes | 2 | 3 | 3 | 21 | ||
no | 1 | 7 | 4 | 16 | |||
Histological type of tumors | oligodendroglial | 0 | 1 | 3 | 0 | ||
astrocytic | 3 | 9 | 4 | 37 | |||
Number of smokers | number of cases | 48 | 1 | 6 | 4 | 22 | Pack-year difference between K and G1–G4 B |
pack-years (median) | 37.5 | 0 C | 8 | 26 | 38.5 | No statistically significant difference (p > 0.05) | |
IDH 1/2 mutation | yes | 0 | 10 | 5 | 10 | ||
no | 3 | 0 | 2 | 27 | |||
p53 mutation | yes | 1 | 10 | 7 | 34 | ||
no | 2 | 0 | 0 | 3 | |||
EGFR expression | yes | 0 | 6 | 2 | 29 | ||
no | 3 | 4 | 5 | 8 |
Parameter/Biomarker | MMP-1 (ng/mL) | UCH-L1 (ng/mL) | Proteasome (µg/mL) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
K | G1 | G2 | G3 | G4 | K | G1 | G2 | G3 | G4 | K | G1 | G2 | G3 | G4 | |
Median | 19.43 | 17.68 | 17.49 | 41.22 | 42.73 | 6.24 | 3.08 | 6.57 | 27.73 | 25.16 | 12.59 | 6.81 | 10.67 | 29.87 | 30.73 |
Q1 | 17.22 | 17.33 | 14.28 | 38.69 | 37.16 | 4.83 | 3.03 | 6.06 | 21.89 | 22.83 | 10.66 | 6.66 | 8.08 | 25.81 | 26.77 |
Q3 | 21.70 | 17.82 | 19.34 | 41.77 | 47.65 | 7.42 | 3.20 | 10.82 | 29.55 | 27.67 | 14.76 | 8.35 | 12.91 | 35.57 | 29.49 |
MIN | 10.24 | 16.98 | 8.32 | 20.55 | 21.06 | 3.43 | 2.97 | 5.54 | 14.39 | 19.89 | 7.19 | 6.51 | 6.90 | 17.66 | 14.56 |
MAX | 24.40 | 17.96 | 24.46 | 43.23 | 52.15 | 9.66 | 3.31 | 17.15 | 30.17 | 29.98 | 21.52 | 9.89 | 17.68 | 40.42 | 45.25 |
Parameter | MMP-1 Concentration (ng/mL) | UCH-L1 Concentration (ng/mL) | 20S Proteasome Concentration (µg/mL) | ||||||
---|---|---|---|---|---|---|---|---|---|
Range | Median | p-Value | Range | Median | p-Value | Range | Median | p-Value | |
Tumor grade (G1–G2 vs. G3–G4) | |||||||||
G1 (3) | 16.98–17.96 | 17.68 | <<0.01 | 2.97–3.31 | 3.08 | <<0.01 | 6.51–9.89 | 6.81 | <<0.01 |
G2 (10) | 8.32–24.46 | 17.49 | 5.54–17.15 | 6.56 | 6.90–17.68 | 10.67 | |||
G3 (7) | 20.55–43.23 | 41.22 | 14.39–30.17 | 27.73 | 17.66–40.42 | 29.87 | |||
G4 (37) | 21.06–52.15 | 42.73 | 19.89–29.98 | 25.16 | 14.56–45.25 | 30.73 | |||
Tumor size (cm2) | |||||||||
<15 (17) | 8.32–47.78 | 36.73 | >0.05 (NS) | 2.97–30.14 | 23.03 | >0.05 (NS) | 6.81–44.28 | 28.74 | >0.05 (NS) |
>15 (14) | 13.97–51.98 | 42.32 | 3.08–29.38 | 23.24 | 6.51–39.78 | 30.50 | |||
The presence of other neoplasms in the family | |||||||||
yes (26) | 8.32–52.15 | 39.67 | >0.05 (NS) | 6.31–30.17 | 22.51 | >0.05 (NS) | 7.21–45.25 | 27.92 | >0.05 (NS) |
no (29) | 9.03–51.98 | 38.43 | 2.97–30.14 | 24.02 | 6.51–44.28 | 28.34 | |||
Concomitant non-cancerous diseases | |||||||||
yes (29) | 9.03–51.23 | 40.46 | >0.05 (NS) | 2.97–29.03 | 23.21 | >0.05 (NS) | 6.51–45.25 | 28.34 | >0.05 (NS) |
no (28) | 8.32–52.15 | 38.19 | 3.31–30.17 | 24.07 | 6.90–44.77 | 27.92 |
Age–MMP-1 | |||||
G1 | G2 | G3 | G4 | All Samples | |
RSpearman | 0.5 | −0.59 | −0.02 | −0.18 | 0.34 |
p | >0.05 | >0.05 | >0.05 | >0.05 | <0.01 |
Age–UCH-L1 | |||||
G1 | G2 | G3 | G4 | All Samples | |
RSpearman | 0.5 | −0.26 | −0.29 | −0.04 | 0.31 |
p | >0.05 | >0.05 | >0.05 | >0.05 | <0.05 |
Age–20S Proteasome | |||||
G1 | G2 | G3 | G4 | All Samples | |
RSpearman | 1 | 0.13 | 0.31 | 0.05 | 0.48 |
p | - | >0.05 | >0.05 | >0.05 | <0.01 |
Tumor Size–MMP-1 | |||||
G1 | G2 | G3 | G4 | All Samples | |
RSpearman | - | - | -0.4 | 0.36 | 0.24 |
p | - | - | >0.05 | >0.05 | >0.05 |
Tumor Size–UCH-L1 | |||||
G1 | G2 | G3 | G4 | All Samples | |
RSpearman | - | 0.4 | - | 0.09 | −0.11 |
p | - | >0.05 | - | >0.05 | >0.05 |
Tumor Size–20S Proteasome | |||||
G1 | G2 | G3 | G4 | All Samples | |
RSpearman | - | - | 0.8 | 0.08 | 0.04 |
p | - | - | >0.05 | >0.05 | >0.05 |
G1 | |||
MMP-1–UCH-L1 | MMP-1–Proteasome | UCH-L1–Proteasome | |
RSpearman | - | 0.5 | 0.5 |
p | - | >0.05 | >0.05 |
G2 | |||
MMP-1–UCH-L1 | MMP-1–Proteasome | UCH-L1–Proteasome | |
RSpearman | 0.07 | 0.07 | 0.14 |
p | >0.05 | >0.05 | >0.05 |
G3 | |||
MMP-1–UCH-L1 | MMP-1–Proteasome | UCH-L1–Proteasome | |
RSpearman | 0.32 | - | 0.25 |
p | >0.05 | >0.05 | >0.05 |
G4 | |||
MMP-1–UCH-L1 | MMP-1–Proteasome | UCH-L1–Proteasome | |
RSpearman | 0.32 | 0.16 | 0.21 |
p | >0.05 | >0.05 | >0.05 |
All samples | |||
MMP-1–UCH-L1 | MMP-1–Proteasome | UCH-L1–Proteasome | |
RSpearman | 0.63 | 0.59 | 0.61 |
p | <<0.01 | <<0.01 | <<0.01 |
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Preoperative Diagnostic Method/Technique | Application | Ref. |
---|---|---|
MRI of the brain with various modifications (including the use of a gadolinium-based contrast agent) | The gold standard in the diagnosis of brain gliomas. | [2] |
Perfusion MRI and PET | Determination of metabolic hotspots for tumor tissue harvesting when a biopsy is considered, rather than open resection. | [3] |
Electroencephalography | Monitoring of epilepsy as the cause of the neoplastic tumor; helps in determining the cause of consciousness disorders. | [4] |
Liquid biopsy | Detection of cell-free DNA of a brain tumor; liquid biopsy methods for screening, early diagnosis, and pre-operative diagnosis require further development to confirm their effectiveness. | [4] |
Marker | Histological Type of Tumor | Characteristics of Marker Changes | Ref. |
---|---|---|---|
BRAF | Pilocytic astrocytoma | Mutations or fusions in the BRAF gene. | [6] |
IDH1 CIC FUBP1 | Oligodendroglioma | The IDH1 mutation and the 1p19q chromosome co-deletion correlate with higher survival during the administration of combined chemotherapy and radiotherapy. Moreover, oligodendrogliomas are characterized by unique mutations of the CIC and FUBP1 genes. | |
IDH p53 | Astrocytoma, primary glioblastoma | The development of astrocytomas through the IDH mutation followed by p53. EGFR amplification and loss of PTEN and cyclin-dependent kinase inhibitors in primary glioblastoma. | |
IDH 1p/19q MGMT | Diffuse gliomas | IDH mutation, 1p/19q co-deletion, and MGMT methylation as prognostic markers of diffuse gliomas. | |
MGMT promoter methylation | Anaplastic glioma, glioblastoma multiforme (GBM) | MGMT promoter methylation is a prognostic marker for low-grade gliomas (about 93%), anaplastic gliomas (50–80%), primary glioblastomas (about 40%), and secondary glioblastomas (about 70%). | [7] |
ATRX | Secondary glioblastoma, low-grade glioma | Mutation or deletion of the ATRX gene, which is also found in IDH mutant tumors that are not 1p/19q co-deleted. | [8] |
EGFR | Primary glioblastoma | Amplification, mutation, and mutual exclusion of p53 mutations. EGFR amplification occurs in approximately 40% of GBM patients and correlates with high-grade neoplasm. | |
HIF-1α | High-grade glioma | Overexpression. | |
NF1 | Mesenchymal and pilocytic astrocytomas Primary glioblastoma | About 20% mutation or deletion in the primary glioblastoma. Close association of NF1 with the mesenchymal subtype. | |
VEGF | Mesenchymal glioma | Overexpression correlates with a higher grade of glioma. | |
ELDT1 | Mesenchymal and high-grade gliomas | Overexpression. |
Analytical Characteristics of the Methods Used | Characteristics of the Quantification Procedures Used | |||||
---|---|---|---|---|---|---|
Biomarker | Method | Analytical Characteristic | Ref. | Biological Material | Dilution | pH |
MMP-1 | SPRi biosensor (non-fluidic) | Cantibody = 170 ng/mL | [23] | Blood plasma (blood centrifuged at 3000 rpm for 15 min, then stored at −80 °C) | K | 7.40 |
LOD = 9 pg/mL | G1 ×15 | |||||
LOQ = 18 pq/mL | G2 | |||||
pH = 7.40 | G3 ×30 | |||||
LR: 0.1–2.5 ng/mL | G4 | |||||
UCH-L1 | Cantibody = 10 µg/mL | [24] | K | |||
LOD = 0.06 ng/mL | G1 ×10 | |||||
LOQ = 0.19 ng/mL | G2 | |||||
pH = 7.40 | G3 ×15 | |||||
LR: 0.5–3.0 ng/mL | G4 | |||||
20S Proteasome | CPSI = 25 µg/mL | [25] | K | |||
LOD = 0.1 µg/mL | G1 ×5 | |||||
LOQ = 0.37 µg/mL | G2 | |||||
pH = 7.40 | G3 ×10 | |||||
LR: 1.4–7.0 µg/mL | G4 |
AUC | p-Value | PPV (%) | NPV (%) | Sensitivity (%) | Specificity (%) | Cut-Off Point | |
---|---|---|---|---|---|---|---|
MMP-1 | 0.83 | <<0.01 | 100 | 77.42 | 75.43 | 100 | 24.46 |
UCH-L1 | 0.89 | <<0.01 | 100 | 82.76 | 82.46 | 100 | 11.34 |
20S Proteasome | 0.83 | <<0.01 | 95.56 | 76.67 | 75.44 | 95.83 | 17.66 |
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Oldak, L.; Chludzinska-Kasperuk, S.; Milewska, P.; Grubczak, K.; Reszec, J.; Gorodkiewicz, E. MMP-1, UCH-L1, and 20S Proteasome as Potential Biomarkers Supporting the Diagnosis of Brain Glioma. Biomolecules 2022, 12, 1477. https://doi.org/10.3390/biom12101477
Oldak L, Chludzinska-Kasperuk S, Milewska P, Grubczak K, Reszec J, Gorodkiewicz E. MMP-1, UCH-L1, and 20S Proteasome as Potential Biomarkers Supporting the Diagnosis of Brain Glioma. Biomolecules. 2022; 12(10):1477. https://doi.org/10.3390/biom12101477
Chicago/Turabian StyleOldak, Lukasz, Sylwia Chludzinska-Kasperuk, Patrycja Milewska, Kamil Grubczak, Joanna Reszec, and Ewa Gorodkiewicz. 2022. "MMP-1, UCH-L1, and 20S Proteasome as Potential Biomarkers Supporting the Diagnosis of Brain Glioma" Biomolecules 12, no. 10: 1477. https://doi.org/10.3390/biom12101477