Genetic Variants in Oxidative Stress-Related Genes and Their Impact on Prognosis and Treatment Response in Chronic Myeloid Leukemia Patients
Abstract
1. Introduction
2. Results
2.1. Characteristics of CML Patients
2.2. Genetic Variants Associated with TKI Response and BCR::ABL1 Mutational Status
2.3. Impacts of Studied SNVs on Progression and Overall Survival
2.4. Influence of Studied SNVs on Gene Expression Levels and Protein Function
3. Discussion
4. Materials and Methods
4.1. Study Population
4.2. Gene and SNV Selection
4.3. Genotyping
4.4. Genetic Analysis
4.5. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ASO-PCR | Allele-specific oligonucleotide polymerase chain reaction |
CAT | Catalase |
CI | Confidence interval |
CML | Chronic myeloid leukemia |
ELN | European Leukemia Net |
GP | Genotypic profile |
GPX1 | Glutathione peroxidase 1 |
HR | Hazard ratio |
HWE | Hardy–Weinberg equilibrium |
KEAP1 | Kelch-like ECH-associated protein 1 |
M | Major allele |
m | Minor allele |
MAF | Frequency of the minor allele |
MCD | Codominant model |
MD | Dominant model |
MgCL2 | Magnesium chloride |
MOD | Overdominant model |
MR | Recessive model |
NFE2L2 | Nuclear factor erythroid 2-related factor 2 gene |
NRF2 | Nuclear factor erythroid 2-related factor 2 |
OD | Odds ratio |
OS | Oxidative stress |
RFLP-PCR | Restriction fragment length polymorphism polymerase chain reaction |
Ref | Reference allele or genotype |
ROS | Reactive oxygen species |
SNV | Single nucleotide variants |
SOD2 | Superoxide dismutase [Mn], mitochondrial |
Ta | Annealing temperature |
TETRA-ARMS-PCR | Tetra-primer amplification refractory mutation system-polymerase chain reaction |
TF | Transcription factor |
TKI | Tyrosine kinase inhibitor |
WHO | World Health Organization |
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Characteristics | CML | ||||||
---|---|---|---|---|---|---|---|
All Patients (n = 187) | TKI Responders (n = 138) | TKI Resistors (n = 49) | p Value | ||||
Demographic Features | |||||||
Gender (%) | |||||||
Male | 110 | (58.8) | 78 | (56.5) | 32 | (65.3) | p = 0.294 * |
Female | 77 | (41.2) | 60 | (43.5) | 17 | (34.7) | |
Age (years) | |||||||
Median | 54 | 54 | 50 | p = 0.408 # | |||
Range | 15–86 | 15–86 | 18–79 | ||||
Clinical Features | |||||||
Phase of Disease | |||||||
Chronic Phase (%) | 177 | (94.6) | 131 | (94.9) | 46 | (93.9) | p = 0.091 * |
Accelerate Phase (%) | 5 | (2.7) | 5 | (3.6) | – | – | |
Blast Crisis (%) | 5 | (2.7) | 2 | (1.5) | 3 | (6.1) | |
Scoring Systems | |||||||
Sokal Score | (n = 138) | (n = 105) | (n = 33) | ||||
Low Risk (%) | 75 | (54.4) | 59 | (56.2) | 16 | (48.5) | p = 0.712 * |
Intermediate Risk (%) | 45 | (32.6) | 33 | (31.4) | 12 | (36.4) | |
High Risk (%) | 18 | (13.0) | 13 | (12.4) | 5 | (15.1) | |
Euro Score | (n = 138) | (n = 105) | (n = 33) | ||||
Low Risk (%) | 100 | (72.5) | 79 | (75.2) | 21 | (63.7) | p = 0.266 * |
Intermediate Risk (%) | 32 | (23.2) | 21 | (20.0) | 11 | (33.3) | |
High Risk (%) | 6 | (4.3) | 5 | (4.8) | 1 | (3.0) | |
EUTOS Score | (n = 136) | (n = 104) | (n = 32) | ||||
Low Risk (%) | 119 | (87.5) | 92 | (88.5) | 27 | (84.4) | p = 0.528 * |
High Risk (%) | 17 | (12.5) | 12 | (11.5) | 5 | (15.6) | |
First-Line TKI | |||||||
Imatinib (%) | 178 | (95.2) | 129 | (93.5) | 49 | (100.0) | p = 0.700 * |
Other TKI (%) | 9 | (4.8) | 9 | (6.5) | – | – | |
Number of TKIs during Treatment | |||||||
1 TKI (%) | 138 | (73.8) | 138 | (100.0) | – | – | p < 0.001 * |
2 TKIs (%) | 37 | (19.8) | – | – | 37 | (75.5) | |
≥3 TKIs (%) | 12 | (6.4) | – | – | 12 | (24.5) | |
Mutations on BCR::ABL1 | (n = 104) | (n = 69) | (n = 35) | ||||
Present (%) | 22 | (21.2) | 11 | (15.9) | 11 | (31.4) | p = 0.068 * |
Absence (%) | 82 | (78.8) | 58 | (84.1) | 24 | (68.6) | |
Disease Evolution | |||||||
Progression (%) | 8 | (4.3) | – | – | 8 | (16.3) | p < 0.001 * |
No Progression (%) | 179 | (95.7) | 138 | (100.0) | 41 | (83.7) | |
Overall Survival | (n = 194) | (n = 138) | (n = 49) | ||||
Death (%) | 27 | (14.4) | 12 | (8.7) | 15 | (30.6) | p < 0.001 * |
Survive (%) | 160 | (85.6) | 126 | (91.3) | 34 | (69.4) |
GPX1 rs1050450 | KEAP1 rs113540846 | |||
---|---|---|---|---|
Allele G | Allele A * | Allele G | Allele A * | |
TKI-sensitive | 155 | 115 | 190 | 44 |
TKI-resisitant | 67 | 27 | 66 | 0 |
OR (95% CI) | 1.841 (1.108–3.059) | 31.07 (1.886–511.9) | ||
p value | 0.020 | <0.0001 |
Gene: dbSNV | n | % | OR (95% CI) | p Value | n | % | ||
---|---|---|---|---|---|---|---|---|
GPX1 rs1050450 | TKI-resistant | TKI-sensitive | ||||||
GG | 25 | 53.2 | Ref. | 46 | 34.1 | |||
GA | 17 | 36.2 | 0.497 (0.241–1.024) | 0.058 | 63 | 46.7 | ||
AA | 5 | 10.6 | 0.354 (0.121–1.036) | 0.058 | 26 | 19.3 | ||
GG (MD) | 2.199 (1.120–4.316) | 0.022 | ||||||
AA (MR) | 0.499 (0.180–1.386) | 0.182 | ||||||
GA (MOD) | 0.648 (0.327–1.284) | 0.213 | ||||||
NFE2L2 rs4893819 | 3 or more TKIs | 2 TKIs | ||||||
CC | 3 | 37.3 | Ref. | 11 | 35.5 | |||
CT | 8 | 72.7 | 2.933 (0.605–14.231) | 0.182 | 10 | 32.3 | ||
TT | 0 | 0.0 | - | - | 10 | 32.3 | ||
CC (MD) | 0.682 (0.150–3.109) | 0.621 | ||||||
TT (MR) | - | - | ||||||
CT (MOD) | 5.600 (1.218–25.751) | 0.027 | ||||||
NFE2L2 rs13001694 | With mutation | Without mutation | ||||||
AA | 1 | 7.7 | Ref. | 15 | 35.7 | |||
AG | 12 | 92.3 | 8.571 (1.004–73.210) | 0.050 | 21 | 50 | ||
GG | 0 | 0.0 | - | - | 6 | 14.3 | ||
AA (MD) | 0.150 (0.018–1.269) | 0.082 | ||||||
GG (MR) | - | - | ||||||
AG (MOD) | 12.000 (1.429–100.754) | 0.022 |
Gene: dbSNV | n | % | OR (95% CI) | p-Value | n | % | ||
---|---|---|---|---|---|---|---|---|
CAT rs1001179 | Death | Survival | ||||||
CC | 4 | 33.3 | Ref. | 5 | 8.9 | |||
CT | 3 | 25.0 | 0.163 (0.027–0.969) | 0.046 | 23 | 41.1 | ||
TT | 5 | 41.7 | 0.223 (0.044–1.131) | 0.07 | 28 | 50.0 | ||
CC (MD) | 5.100 (1.125–23.117) | 0.035 | ||||||
TT (MR) | 0.714 (0.202–2.522) | 0.601 | ||||||
CT (MOD) | 0.478 (0.117–1.961) | 0.306 |
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Alves, R.; Ventura, F.; Jorge, J.; Marques, G.; Coucelo, M.; Diamond, J.; Oliveiros, B.; Pereira, A.; Freitas-Tavares, P.; Almeida, A.M.; et al. Genetic Variants in Oxidative Stress-Related Genes and Their Impact on Prognosis and Treatment Response in Chronic Myeloid Leukemia Patients. Int. J. Mol. Sci. 2025, 26, 5682. https://doi.org/10.3390/ijms26125682
Alves R, Ventura F, Jorge J, Marques G, Coucelo M, Diamond J, Oliveiros B, Pereira A, Freitas-Tavares P, Almeida AM, et al. Genetic Variants in Oxidative Stress-Related Genes and Their Impact on Prognosis and Treatment Response in Chronic Myeloid Leukemia Patients. International Journal of Molecular Sciences. 2025; 26(12):5682. https://doi.org/10.3390/ijms26125682
Chicago/Turabian StyleAlves, Raquel, Filipa Ventura, Joana Jorge, Gilberto Marques, Margarida Coucelo, Joana Diamond, Bárbara Oliveiros, Amélia Pereira, Paulo Freitas-Tavares, António M. Almeida, and et al. 2025. "Genetic Variants in Oxidative Stress-Related Genes and Their Impact on Prognosis and Treatment Response in Chronic Myeloid Leukemia Patients" International Journal of Molecular Sciences 26, no. 12: 5682. https://doi.org/10.3390/ijms26125682
APA StyleAlves, R., Ventura, F., Jorge, J., Marques, G., Coucelo, M., Diamond, J., Oliveiros, B., Pereira, A., Freitas-Tavares, P., Almeida, A. M., Gonçalves, A. C., & Sarmento-Ribeiro, A. B. (2025). Genetic Variants in Oxidative Stress-Related Genes and Their Impact on Prognosis and Treatment Response in Chronic Myeloid Leukemia Patients. International Journal of Molecular Sciences, 26(12), 5682. https://doi.org/10.3390/ijms26125682