DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome—Relevance as Complementary Prognostic Biomarkers
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Sample Preparation
2.3. Uric Acid Determinations
2.4. Vitamin A and E Measurements
2.5. Reduced Glutathione Quantification
2.6. Total Antioxidant Status Evaluation
2.7. Antioxidant Enzyme Activity Determination
2.8. Lipid Peroxidation Measurements
2.9. Plasmatic Nitric Oxide Quantification
2.10. Plasmatic Peroxide Quantification
2.11. Plasmatic 8-Hydroxy-2-Deoxyguanosine Quantification
2.12. Global DNA Methylation Analysis
2.13. Methylation Pattern of Tumor Suppressor Genes
2.14. Statistical Analysis
3. Results
3.1. Biodemographic and Clinical Characteristics of MDS Patients
3.2. Oxidative Stress Levels in MDS Patients
3.3. DNA Methylation Status in MDS Patients
3.4. Oxidative Stress and DNA Methylation as MDS Diagnostic Biomarkers
3.5. Correlation between Oxidative Stress and DNA Methylation in MDS Patients
3.6. Association of Oxidative Stress and DNA Methylation with MDS Clinical Outcome
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Characteristics | MDS (n = 66) | Controls (n = 26) | ||
---|---|---|---|---|
Demographic Features | ||||
Gender (%) | ||||
Male | 26 | (39.9%) | 12 | (46.2%) |
Female | 40 | (60.1%) | 14 | (53.8%) |
Age (years) | ||||
Median | 74 | 67 | ||
Range | 22–89 | 32–79 | ||
Clinical features | ||||
Hematological parameters (median, range) | ||||
WBC (×109/L) | 3.5 | (1.3–13.0) | ||
Hb (g/L) | 10.6 | (5.4–16.0) | ||
Platelets (×109/L) | 98 | (12–324) | ||
WHO 2016 classification | ||||
MDS-SLD (%) | 9 | (13.6) | ||
MDS-RS (%) | 10 | (15.2) | ||
MDS-MD (%) | 40 | (60.6) | ||
MDS-EB (%) | 7 | (10.6) | ||
IPSS-R risk groups | ||||
Lower-risk (IPSS-R score ≤3.5) | 38 | |||
Higher-risk (IPSS-R score >3.5) | 13 | |||
Not recorded | 15 | |||
Cytogenetics | ||||
Good | 37 | |||
Intermediate | 11 | |||
Poor | 2 | |||
Not recorded | 15 |
Parameter | MDS-SLD Median (Q1–Q3) | MDS-RS Median (Q1–Q3) | MDS-MD Median (Q1–Q3) | MDS-EB Median (Q1–Q3) | p-Value |
---|---|---|---|---|---|
Peroxides (µM) | 2.27 (1.70–4.02) | 4.59 (3.03–5.85) | 4.54 (3.48–6.07) | 4.34 (2.62–5.92) | 0.048 |
Peroxide/TAS ratio | 2.30 (1.40–4.15) | 4.40 (2.65–5.78) | 4.75 (3.50–6.68) | 4.50 (2.40–6.50) | 0.036 |
Condition | Methylation Frequency | |||||||
---|---|---|---|---|---|---|---|---|
P15 | P16 | DAPK | KEAP1 | |||||
n | % | n | % | n | % | n | % | |
MDS | 32/66 | 48.5 ** | 13/66 | 19.7 | 28/66 | 42.4 *** | 26/66 | 33.3 * |
MDS-SLD | 3/9 | 33.3 | 3/9 | 11.1 | 3/9 | 33.3 | 1/9 | 11.1 |
MDS-RS | 4/10 | 40.0 | 4/10 | 10.0 | 7/10 | 70.0 | 2/10 | 20.0 |
MDS-MD | 20/40 | 50.0 | 20/40 | 20.0 | 14/40 | 35.0 | 17/40 | 42.5 |
MDS-EB | 5/7 | 71.4 | 3/7 | 42.9 | 4/7 | 57.1 | 2/7 | 28.6 |
Controls | 3/26 | 11.5 | 1/26 | 3.8 | 0/26 | 0.0 | 3/26 | 11.5 |
TP53 | MGMT | 1 ≥ methylated genes | 2 ≥ methylated genes | |||||
n | % | n | % | n | % | n | % | |
MDS | 0/66 | 0.0 | 0/66 | 0.0 | 43/66 | 65.2 *** | 32/66 | 48.5 *** |
MDS-SLD | 0/9 | 0.0 | 0/9 | 0.0 | 4/9 | 44.4 | 1/9 | 11.1 |
MDS-RS | 0/10 | 0.0 | 0/10 | 0.0 | 5/10 | 70.0 | 3/10 | 30.0 |
MDS-MD | 0/40 | 0.0 | 0/40 | 0.0 | 29/40 | 72.5 | 23/40 | 57.5 |
MDS-EB | 0/7 | 0.0 | 0/7 | 0.0 | 5/7 | 71.4 | 5/7 | 71.4 |
Controls | 0/26 | 0.0 | 0/26 | 0.0 | 4/26 | 15.4 | 0/26 | 0.0 |
Biomarkers | Univariate Analysis | Multivariate Analysis | ||||
---|---|---|---|---|---|---|
OR | 95% CI | p-Value | OR | 95% CI | p-Value | |
Peroxide | 3.36 | 1.96–5.76 | <0.001 | 1.31 | 1.23–1.45 | 0.008 |
8-OHdG | 1.27 | 1.43–1.41 | <0.001 | 1.23 | 1.01–1.59 | 0.041 |
Peroxide/TAS | 2.54 | 1.61–3.99 | <0.001 | – | ||
NO | 1.18 | 1.05–1.31 | 0.004 | – | ||
NO/TAS | 1.11 | 1.02–1.21 | 0.017 | – | ||
5-mC | 2.43 | 1.62–3.64 | <0.001 | 2.13 | 1.30–3.48 | 0.003 |
5-hmC | 1.54 | 1.14–2.09 | 0.005 | – | ||
LINE-1 | 0.83 | 0.75–0.91 | <0.001 | – | ||
Methylated p15 | 8.42 | 3.85–9.40 | <0.001 | – | ||
Methylated KEAP1 | 3.83 | 1.04–7.18 | 0.044 | – | ||
2 ≥ methylated genes | 7.51 | 4.59–9.34 | <0.001 | 4.52 | 3.39–8.80 | <0.001 |
Biomarkers | AUC | Cut-Off | |||||
---|---|---|---|---|---|---|---|
Value (95% CI) | p-Value | Value | SEN (%) | SPE (%) | PPV (%) | NPV (%) | |
Peroxide (µM) | 0.877 (0.800–0.955) | <0.001 | 3.28 | 73 | 92 | 96 | 77 |
8-OHdG (ng/mL) | 0.863 (0.790–0.937) | <0.001 | 34.7 | 72 | 92 | 96 | 80 |
5-mC (%) | 0.936 (0.887–0.984) | <0.001 | 0.48 | 82 | 96 | 93 | 78 |
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Gonçalves, A.C.; Alves, R.; Baldeiras, I.; Marques, B.; Oliveiros, B.; Pereira, A.; Nascimento Costa, J.M.; Cortesão, E.; Mota Vieira, L.; Sarmento Ribeiro, A.B. DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome—Relevance as Complementary Prognostic Biomarkers. Cancers 2021, 13, 3138. https://doi.org/10.3390/cancers13133138
Gonçalves AC, Alves R, Baldeiras I, Marques B, Oliveiros B, Pereira A, Nascimento Costa JM, Cortesão E, Mota Vieira L, Sarmento Ribeiro AB. DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome—Relevance as Complementary Prognostic Biomarkers. Cancers. 2021; 13(13):3138. https://doi.org/10.3390/cancers13133138
Chicago/Turabian StyleGonçalves, Ana Cristina, Raquel Alves, Inês Baldeiras, Bárbara Marques, Bárbara Oliveiros, Amélia Pereira, José Manuel Nascimento Costa, Emília Cortesão, Luisa Mota Vieira, and Ana Bela Sarmento Ribeiro. 2021. "DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome—Relevance as Complementary Prognostic Biomarkers" Cancers 13, no. 13: 3138. https://doi.org/10.3390/cancers13133138