Genetic polymorphisms as predictors of methotrexate toxicity: literature review

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Abstract

Background. A significant advancement in the treatment of high-grade aggressive non-Hodgkin’s lymphomas and acute lymphoblastic leukemia is the inclusion of high-dose (1000–5000 mg/m2) methotrexate in the treatment protocol. This approach has significantly increased the long-term survival rate, but it has been associated with toxicity, requiring supportive care. Factors that predict toxicity were identified, including genes involved in the metabolism (MTHFR) or transport (SLCO1B1) of methotrexate. The analysis of methotrexate metabolism has identified additional genes responsible for the elimination of this drug, allowing for more effective prevention and treatment of methotrexate-associated toxicity.

Aim. To study the genetic polymorphisms of enzymes involved in the methotrexate metabolism and associated toxicity in the treatment of pediatric acute lymphoblastic leukemia and non-Hodgkin’s lymphomas.

Materials and methods. Data were analyzed in specialized medical databases such as Pubmed, Scopus, Web of Science, Frontiers, and Google Scholar from 2001 to 2024.

Results. The main predictors of high-dose methotrexate-associated toxicity are gene polymorphisms in MTHFR, SLCO1B1, ARID5B.

Conclusion. Despite the contradictory data presented in the literature, it is important to consider the detection of polymorphisms during high-dose methotrexate treatment in order to administer timely supportive care and prevent significant toxicity.

About the authors

G. A. Radzhabova

I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University)

ORCID iD: 0009-0008-8297-3629

Build. 1, 8 Trubetskaya St., Moscow 119991

Russian Federation

T. T. Valiev

I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University); N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Author for correspondence.
Email: timurvaliev@mail.ru
ORCID iD: 0000-0002-1469-2365

Timur T. Valiev.

Build. 1, 8 Trubetskaya St., Moscow 119991; 24 Kashirskoe Shosse, Moscow 115522

Russian Federation

Yu. E. Ryabukhina

Clinical Hospital “Lapino” of the “Mother and Child” Group of companies

ORCID iD: 0000-0001-8443-8816

111 1st Uspenskoe Shosse, Lapino, Moscow region 143081

Russian Federation

M. I. Savelyeva

Yaroslavl State Medical University, Ministry of Health of Russia

ORCID iD: 0000-0002-2373-2250

5 Revolyutsionnaya St., Yaroslavl 150000

Russian Federation

Sh. P. Abdullaev

Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia

ORCID iD: 0000-0001-9001-1499

Build. 1, 2/1 Barrikadnaya St., Moscow 125993

Russian Federation

O. D. Gurieva

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

ORCID iD: 0000-0002-0050-0721

24 Kashirskoe Shosse, Moscow 115522

Russian Federation

P. A. Zeynalova

I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University); Clinical Hospital “Lapino” of the “Mother and Child” Group of companies

ORCID iD: 0000-0003-1564-424X

Build. 1, 8 Trubetskaya St., Moscow 119991; 111 1st Uspenskoe Shosse, Lapino, Moscow region 143081

Russian Federation

References

  1. Rocha J.M., Xavier S.G., de Lima Souza M.E. et al. Current strategies for the detection of minimal residual disease in childhood acute lymphoblastic leukemia. Mediterr J Hematol Infect Dis 2016;8(1):e2016024. doi: 10.4084/MJHID.2016.024
  2. World Health Organization (WHO). International Agency for Research on Cancer 2023. GLOBOCAN 2020: Estimated number of new cases and deaths in 2020, World, both sexes, ages 0–19. Available at: https://gco.iarc.fr.
  3. Hunger S.P., Mullighan C.G. Acute lymphoblastic leukemia in children. N Engl J Med 2015;373(16):1541–52. doi: 10.1056/nejmra1400972
  4. Pui C.H., Evans W.E. A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol 2013;50(3):185–96. doi: 10.1053/j.seminhematol.2013.06.007
  5. Frei E., Freireich E.J., Gehan E. et al. Studies of sequential and combination antimetabolite therapy in acute leukemia: 6-mercaptopurine and methotrexate. Blood 1961;18(4):431–54.
  6. Pavlovic S., Kotur N., Stankovic B. et al. Pharmacogenomic and pharmacotranscriptomic profiling of childhood acute lymphoblastic leukemia: Paving the way to personalized treatment. Genes 2019;10(3):E191. doi: 10.3390/genes10030191
  7. Gervasini G., Vagace J.M. Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia. Front Genet 2012;3:249. doi: 10.3389/fgene.2012.00249
  8. Moriyama T., Relling M.V., Yang J.J. Inherited genetic variation in childhood acute lymphoblastic leukemia. Blood 2015;125(26):3988–995. doi: 10.1182/blood-2014-12-580001
  9. Kuleva S.A., Ivanova S.V., Novik A.V. et al. The use of active detoxification for delayed MTX elimination after high-dose infusion in a child with osteogenic sarcoma: a clinical case. Rossiyskiy zhurnal detskoy gematologii i onkologii = Russian Journal of Pediatric Hematology and Oncology 2017;4(3)58–63. (In Russ.). doi: 10.17650/2311-1267-2017-4-3-58-63
  10. Mikkelsen T.S., Thorn C.F., Yang J.J. et al. PharmGKB summary: methotrexate pathway. Pharmacogenet Genomics 2011;21(10): 679–86. doi: 10.1097/FPC.0b013e328343dd93
  11. Yang L., Wu H., Gelder T.V. et al. SLCO1B1 rs4149056 genetic polymorphism predicting methotrexate toxicity in Chinese patients with non-Hodgkin lymphoma. Pharmacogenomics 2017;18(17):1557–62. doi: 10.2217/pgs-2017-0110
  12. Singh R.K., van Haandel L., Kiptoo P. et al. Methotrexate disposition, anti-folate activity and efficacy in the collagen-induced arthritis mouse model. Eur J Pharmacol 2019;853:264–74. doi: 10.1016/j.ejphar.2019.03.052
  13. Tukukino C., Wallerstedt S.M. Drug information centre queries and responses about drug interactions over 10 years – a descriptive analysis. Basic Clin Pharmacol Toxicol 2020;126(1):65–74. doi: 10.1111/bcpt.13294
  14. He H.R., Liu P., He G.H. et al. Association between reduced folate carrier G80A polymorphism and methotrexate toxicity in childhood acute lymphoblastic leukemia: A meta-analysis. Leuk Lymphoma 2014;55(12):2793–800. doi: 10.3109/10428194.2014.898761
  15. Gomez-Gomez Y., Organista-Nava J., Villanueva-Flores F. et al. Association between the 5, 10-MTHFR 677C>T and RFC1 80G>A polymorphisms and acute lymphoblastic leukemia. Arch Med Res 2019;50(4):175–80. doi: 10.1016/j.arcmed.2019.07.010
  16. Chiusolo P., Giammarco S., Bellesi S. et al. The role of MTHFR and RFC1 polymorphisms on toxicity and outcome of adult patients with hematological malignancies treated with high-dose methotrexate followed by leucovorin rescue. Cancer Chemother. Pharmacol 2012;69(3):691–6. doi: 10.1007/s00280-011-1751-4
  17. Cwiklinska M., Czogala M., Kwiecinska K. et al. Polymorphisms of SLC19A1 80G>A, MTHFR 677C>T, and tandem TS repeats influence pharmacokinetics, acute liver toxicity, and vomiting in children with acute lymphoblastic leukemia treated with high doses of methotrexate. Front Pediatr 2020;8:307. doi: 10.3389/fped.2020.00307
  18. Gregers J., Christensen I.J., Dalhoff K. et al. The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number. Blood 2010;115:4671–7. doi: 10.1182/blood-2010-01-256958
  19. Rudin S., Marable M., Huang R.S. The promise of pharmacogenomics in reducing toxicity during acute lymphoblastic leukemia maintenance treatment. Genomics Proteomics Bioinformatics 2017;15(2):82–93. doi: 10.1016/j.gpb.2016.11.003
  20. Ferrari M., Guasti L., Maresca A. et al. Association between statin-induced creatine kinase elevation and genetic polymorphisms in SLCO1B1, ABCB1 and ABCG2. Eur J Clin Pharmacol 2014;70(5):539–47. doi: 10.1007/s00228-014-1661-6
  21. Treviño L.R., Shimasaki N., Yang W. et al. Germline genetic variation in anorganic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol 2009;27(35):5972–8. doi: 10.1200/JCO.2008.20.4156
  22. Tirona R.G., Leake B.F., Merino G. et al. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem 2001;276(38):35669–75. doi: 10.1074/jbc.M103792200
  23. Van de Steeg E., van der Kruijssen C.M., Wagenaar E. et al. Methotrexate pharmacokinetics in transgenic mice with liver-specific expression of human organic anion-transporting polypeptide 1B1 (SLCO1B1). Drug Metab Dispos 2009;37(2): 277–81. doi: 10.1124/dmd.108.024315
  24. Smirnov L.P. ATP-binding transport proteins of the ABC family (ATP-binding cassette transporters, ABC). Nomenclature, structure, molecular diversity, function, participation in the functioning of the xenobiotic biotransformation system. Trudy Karelskogo nauchnogo tsentra RAN = Transactions of Karelian Research Centre of Russian Academy of Sciences 2020;(3):5–19. (In Russ.).
  25. Juliano R.L., Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976;455(1):152–62. doi: 10.1016/0005-2736(76)90160-7
  26. Ni L.N., Li J.Y., Miao K.R. et al. Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia. Med Oncol 2011;28(1):265–9. doi: 10.1007/s12032-010-9456-9
  27. Clinical pharmacology for pediatricians: textbook. Eds.: E.V. Shikh, V.N. Drozdova. Moscow: GEOTAR-Media, 2021. 1008 р. (In Russ.).
  28. Kimchi-Sarfaty C., Oh J.M., Kim I.W. et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 2007;315(5811):525–8. doi: 10.1126/science.1135308
  29. Sheng X., Zhang L., Tong N. et al. MDR1 C3435T polymorphism and cancer risk: a meta-analysis based on 39 case-control studies. Mol Biol Rep 2012;39(7):7237–49. doi: 10.1007/s11033-012-1554-7
  30. Wang J., Wang B., Bi J. et al. MDR1 gene C3435T polymorphism and cancer risk: a meta-analysis of 34 case-control studies. J Cancer Res Clin Oncol 2012;138(6):979–8. doi: 10.1007/s00432-012-1171-9
  31. Karathanasis N.V., Choumerianou D.M., Kalmanti M. Gene polymorphisms in childhood ALL. Pediatr Blood Cancer 2009;52(3):318–23. doi: 10.1002/pbc.21825
  32. Faganel Kotnik B., Grabnar I., Bohanec Grabar P. et al. Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma. Eur J Clin Pharmacol 2011;67(10):993–1006. doi: 10.1007/s00228-011-1046-z
  33. Ma C.X., Sun Y.H., Wang H.Y. ABCB1 polymorphisms correlate with susceptibility to adult acute leukemia and response to high-dose methotrexate. Tumor Biol 2015;36:7599–606. doi: 10.1007/s13277-015-3403-5
  34. Van der Straaten R.J., Wessels J.A., De Vries-Bouwstra J.K. et al. Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients. Pharmacogenomics 2007;8(2):141–50. doi: 10.2217/14622416.8.2.141
  35. Sharma S., Das M., Kumar A. et al. Interaction of genes from influx-metabolism-efflux pathway and their influence on methotrexate efficacy in rheumatoid arthritis patients among Indians. Pharmacogenet Genomics 2008;18(12):1041–9. doi: 10.1097/fpc.0b013e328311a8fd
  36. Sharma S., Das M., Kumar A. et al. Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians. Pharmacogenet Genomics 2009;19(10): 823–8. doi: 10.1097/fpc.0b013e328331b53e
  37. Liu S.G., Gao C., Zhang R.D. et al. FPGS rs1544105 polymorphism is associated with treatment outcome in pediatric B-cell precursor acute lymphoblastic leukemia. Cancer Cell Int 2013;29(13):107. doi: 10.1186/1475-2867-13-107
  38. Wang S.M., Sun L.L., Zeng W.X. et al. Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2014;74(2):283–9. doi: 10.1007/s00280-014-2507-8
  39. Jekic B., Vejnovic D., Milic V. et al. Association of 63/91 length polymorphism in the DHFR gene major promoter with toxicity of methotrexate in patients with rheumatoid arthritis. Pharmacogenomics 2016;17(15):1687–91. doi: 10.2217/pgs-2016-0090
  40. Koomdee N., Hongeng S., Apibal S., Pakakasama S. Association between polymorphisms of dihydrofolate reductase and gamma glutamyl hydrolase genes and toxicity of high dose methotrexate in children with acute lymphoblastic leukemia. Asian Pac J Cancer Prev 2012;13(7):3461–4. doi: 10.7314/apjcp.2012.13.7.3461
  41. Ongaro A., De Mattei M., Della Porta M.G. et al. Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival. Haematologica 2009;94(10):1391–8. doi: 10.3324/haematol.2009.008326
  42. Ceppi F., Gagné V., Douyon L. et al. DNA variants in DHFR gene and response to treatment in children with childhood B ALL: revisited in AIEOP-BFM protocol. Pharmacogenomics 2018;19(2):105–12. doi: 10.2217/pgs-2017-0153
  43. Devald I.V., Khodus E.A., Khromova E.B. et al. Allelic polymorphisms of thymidylate synthase gene and their haplotypes as predictors of the therapeutic response to methotrexate in patients with rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice 2019;57(2):149–53. (In Russ.). doi: 10.14412/1995-4484-2019-149-53
  44. Chen Y., Shen Z. Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL. Tumor Biol 2015;36(7):4913–21. doi: 10.1007/s13277-015-3602-0
  45. Oosterom N., Berrevoets M., den Hoed M.A.H. et al. The role of genetic polymorphisms in the thymidylate synthase (TYMS) gene in methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia. Pharmacogenet Genomics 2018;28(10):223–9. doi: 10.1097/FPC.0000000000000352
  46. Kodidela S., Suresh Chandra P., Dubashi B. Pharmacogenetics of methotrexate in acute lymphoblastic leukaemia: why still at the bench level? Eur J Clin Pharmacol 2014;70:253–60. doi: 10.1007/s00228-013-1623-4
  47. Tan Y., Kong Q., Li X. et al. Relationship between methylenetetrahydrofolate reductase gene polymorphisms and methotrexate drug metabolism and toxicity. Transl Pediatr 2023;12(1):31–45. doi: 10.21037/tp-22-671
  48. Lopez-Lopez E., Martin-Guerrero I., Ballesteros J., Garcia-Orad A. A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia. Pharmacogenomics J 2012;13(6):498–506. doi: 10.1038/tpj.2012.44
  49. Huang L., Tissing W.J., de Jonge R. et al. Polymorphisms in folate-related genes: association with side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia. Leukemia 2008;22(9):1798–800. doi: 10.1038/leu.2008.66
  50. Zhao M., Liang L., Ji L. et al. MTHFR gene polymorphisms and methotrexate toxicity in adult patients with hematological malignancies: a meta-analysis. Pharmacogenomics 2016;17(9):1005–17. doi: 10.2217/pgs-2016-0004
  51. Han J., Liu L., Meng L. et al. Effect of polymorphisms of ABCB1 and MTHFR on methotrexate-related toxicities in adults with hematological malignancies. Front Oncol 2021;11:759805. doi: 10.3389/fonc.2021.759805
  52. Ojha R.P., Gurney J.G. Methylenetetrahydrofolate reductase C677T and overall survival in pediatric acute lymphoblastic leukemia: a systematic review. Leuk Lymphoma 2014;55(1):67–73. doi: 10.3109/10428194.2013.792336
  53. Zhao X., Qian M., Goodings C. et al. Molecular mechanisms of ARID5B-mediated genetic susceptibility to acute lymphoblastic leukemia. J Natl Cancer Inst 2022;114(9):1287–95. doi: 10.1093/jnci/djac101
  54. Xu H., Zhao X., Bhojwani D. et al. ARID5B influences antimetabolite drug sensitivity and prognosis of acute lymphoblastic leukemia. Clin Cancer Res 2020;26(1):256–64. doi: 10.1158/1078-0432.CCR-19-0190
  55. Csordas K., Lautner-Csorba O., Semsei A.F. et al. Associations of novel genetic variations in the folate-related and ARID5B genes with the pharmacokinetics and toxicity of high-dose methotrexate in paediatric acute lymphoblastic leukaemia. Br J Haematol 2014;166(3):410–20. doi: 10.1111/bjh.12886
  56. Zhang L.F., Ma Y., Li L. et al. Correlation between ARID5B gene SNP and MTX resistance in children with ALL. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2023;31(2):333–7. doi: 10.19746/j.cnki.issn.1009-2137.2023.02.004
  57. Hoffman J.M., Haidar C.E., Wilkinson M.R. et al. PG4KDS: a model for the clinical implementation of pre-emptive pharmacogenetics. Am J Med Genet C Semin Med Genet 2014;166C(1):45–55. doi: 10.1002/ajmg.c.31391

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СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-36928 от  21.07.2009.