Inherited Variants is a Genetic Determinant of Mercaptopurine/Methotrexate Intolerance in Children With Acute Lymphoblastic Leukemia
Emine Ikbal Atli1, Tuba Eren2, Damla Eker1, Engin Atli1, Selma Demir1, Sinem Yalcintepe1, Hakan Gurkan11Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Türkiye, 2Department of Child Health and Diseases, Faculty of Medicine, Trakya University, Edirne, Türkiye
Objectives: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children with distinctive features across its different subtypes. Although the etiology of ALL has not been fully elucidated, it has been shown that the onset of ALL is partly due to genetic factors. Genes related to drug transport, metabolism, detoxification and DNA repair could influence the cytotoxic effects associated with chemotherapy, including those involved in the transport (e.g., ABCB1, ABCC2, MTHFR and SLCO1B3), and transporter of folate (SLC19A1) of MTX and 6-MP. Likewise, genes involved in DNA-binding transcription factor activity and RNA polymerase II cis-regulatory region sequence-specific DNA binding (NR3C1) and DNA repair (TYMS) have previously been linked with cytotoxicity of 6-MP and/or MTX. Methods: In the current study, we therefore aimed to assess prior associations for 17 selected genetic variants in 5 genes, in a large cohort of 41 ALL patients treated with mercaptopurine (6-MP) and methotrexate (MTX) combination therapy or mono-therapy of whom detailed clinical toxicity datas were available. Results: Among the 17 variants in 5 genes evaluated according to the results of our study, the polymorphisms in rs2893881 (G/A) in ARID5B were closely related to therapy toxicity. To our knowledge, the effect of ARID5B variants on childhood ALL has not been studied in Turkey. Several genome-wide and candidate gene association studies have reported strong associations between ARID5B SNPs and risk of ALL and toxicity to therapeutic drugs in different populations. Conclusion: Finally, one of the most significant findings from this study is that ARID5B germline SNPs related to ALL treatment toxicity. To our knowledge, this is the first report to describe the relationship between ARID5B and ALL treatment response in the context of a preliminary ALL clinical trial. Further investigation of ARID5B variation in line with different ALL treatment regimens is required to improve its value as a prognostic marker. Keywords: ARID5B, childhood leukemia, single nucleotide polymorphism
Cite This Article
Ikbal Atli E, Eren T, Eker D, Atli E, Demir S, Yalcintepe S, Gurkan H. Inherited Variants is a Genetic Determinant of Mercaptopurine/Methotrexate Intolerance in Children With Acute Lymphoblastic Leukemia. EJMI. 2022; 6(4): 436-442
Corresponding Author: Emine Ikbal Atli