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Blood Res (2024) 59:46
Published online December 30, 2024
https://doi.org/10.1007/s44313-024-00033-7
© The Korean Society of Hematology
RAD51 and RAD50 genetic polymorphisms from homologous recombination repair pathway are associated with disease outcomes and organ toxicities in AML
Correspondence to : Mohammad Jafar Sharifi
mjsharifi63@yahoo.com
© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background Acute myeloid leukemia (AML) is a heterogeneous malignancy that responds to various therapies. The sensitivity of leukemia cells to chemotherapy is affected by the DNA damage response (DDR). In this study, we examined the association between RAD51 rs1801320, XRCC3 rs861539, NBS1 rs1805794, MRE11 rs569143, and RAD50 rs2299014 variants of the homologous recombination repair (HRR) pathway and AML outcomes.
Material and methods PCR–RFLP was applied for the genotyping of 67 newly diagnosed cases. We performed Sanger sequencing to confirm the results of RFLP genotyping. Outcomes and organ toxicities were collected and χ2 testing was performed for association analysis.
Results RAD50 variant allele carriers were protected from renal and hepatic toxicities (p = 0.024 and p = 0.045, respectively), and were associated with resistant disease (p = 0.001). RAD51 variant alleles were protected from liver toxicity (p = 0.031) and correlated with disease resistance (p = 0.012).
Conclusion RAD50 rs2299014 and RAD51 rs1801320 polymorphisms may be useful for drug adjustment in AML.
Keywords Acute Myeloid Leukemia, Outcomes, Organ toxicity, Chemotherapy, Pharmacogenetic
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RESEARCH
Blood Res 2024; 59():
Published online December 30, 2024 https://doi.org/10.1007/s44313-024-00033-7
Copyright © The Korean Society of Hematology.
RAD51 and RAD50 genetic polymorphisms from homologous recombination repair pathway are associated with disease outcomes and organ toxicities in AML
Alireza Mohseni1, Gholamreza Toogeh2, Shahrbano Rostami3, Mohammad Faranoush4 and Mohammad Jafar Sharifi5*
1 Thalassemia Research Center, Hemoglobinopthy Institute, Mazandaran University of Medical Sciences, Sari, Iran
2 Department of Internal Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
3 Tehran University of Medical Sciences, Tehran, Iran
4 Pediatric Growth and Development Research Center, Iran University of Medical Sciences, Tehran, Iran
5 Division of Laboratory Hematology and Blood Banking, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Meshkin Fam Street, P.O. Box, Shiraz 71345‑1744, Iran
Correspondence to:Mohammad Jafar Sharifi
mjsharifi63@yahoo.com
© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Abstract
Background Acute myeloid leukemia (AML) is a heterogeneous malignancy that responds to various therapies. The sensitivity of leukemia cells to chemotherapy is affected by the DNA damage response (DDR). In this study, we examined the association between RAD51 rs1801320, XRCC3 rs861539, NBS1 rs1805794, MRE11 rs569143, and RAD50 rs2299014 variants of the homologous recombination repair (HRR) pathway and AML outcomes.
Material and methods PCR–RFLP was applied for the genotyping of 67 newly diagnosed cases. We performed Sanger sequencing to confirm the results of RFLP genotyping. Outcomes and organ toxicities were collected and χ2 testing was performed for association analysis.
Results RAD50 variant allele carriers were protected from renal and hepatic toxicities (p = 0.024 and p = 0.045, respectively), and were associated with resistant disease (p = 0.001). RAD51 variant alleles were protected from liver toxicity (p = 0.031) and correlated with disease resistance (p = 0.012).
Conclusion RAD50 rs2299014 and RAD51 rs1801320 polymorphisms may be useful for drug adjustment in AML.
Keywords: Acute Myeloid Leukemia, Outcomes, Organ toxicity, Chemotherapy, Pharmacogenetic
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Table 1 . Patients characteristics data. Cytogenetic risk classification based on WHO guidelines was provided for only 43 patients with cytogenetic results.
Patient numbers 67 Age (years), median (range) 41(15–65) Gender, no (%) Male 38(56.7) Female 29(43.3) Leukocyte count, 109/L, median (range) 29,900 (400–215,300) Blast (%); peripheral blood, median (range) 39(5–39) Blast (%); Bone Marrow, median (range) 80 (29–98) Hemoglobin g/dL, median (range) 8.9 (3.3–9.7) Platelet,109/L, median (range) 47,000 (1,000–27,000,0) Low-risk karyotype; Inv16, t(8;21) 6 (9%) High-risk Karyotype; del5q, -5, -7, 3q abnormalities and complex 5 (7.5%) Intermediate-risk karyotype; All others 32 (83.5%)
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Table 2 . Correlation of polymorphisms with resistance to induction therapy.
Polymorphism (n) Resistance to induction Therapy (%) OR (95% CI) P.value RAD51 rs1801320 GG (37) 4 (26.7) Reference GC + CC (30) 11(73.3) 4.77(1.33–17.11) 0.012† XRCC3 rs861539 CC (33) 8 (53.3) Reference CT + TT (34) 7(46.7) 0.810(0.256–2.56) 0.72 NBS1 rs1805794 CC (25) 3 (20.0) Reference CG + GG (42) 12 (80.0) 2.93(0.738–11.65) 0.116 MRE11 rs569143 CC(26) 6 (40.0) Reference CG + GG(41) 9 (60.0) 0.938 (0.290–3.03) 0.914 RAD50 rs2299014 GG (39) 3 (20.0) Reference GT + TT (28) 12 (80.0) 9.00(2.22–36.33) 0.001† † Statistically significant difference.
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