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Effects of thymidylate synthase polymorphisms on toxicities associated with high-dose methotrexate in childhood acute lymphoblastic leukemia

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Abstract

Background

High-dose methotrexate (HD- MTX) is the cornerstone of chemotherapy for acute lymphoblastic leukemia (ALL), and one of its target enzymes is Thymidylate Synthase (TYMS). We hypothesized that genetic polymorphisms of TYMS gene would be associated with MTX toxicity in ALL children.

Methods

64 children with ALL were included in this study. Genotyping analysis was conducted on three common polymorphisms: tandem repeats in the promoter-enhancer region (VNTR), 6 bp ins/del (1494del6) in the 5′UTR, and rs2790 A > G in the 3′-untranslated region (3′-UTR). The association between genetic polymorphisms and MTX toxicity was studied.

Results

Genetic polymorphism of TYMS was associated with hematological toxicities but not with non-hematological adverse events. A significant association between TYMS 1494del6 genotypes and incidence of neutropenia (ANC < 1700 mm3), infection and leukopenia was observed. Carriers of the dominant allele (Del) were 6 times more likely to develop neutropenia compared to minor genotype carriers (OR (95% CI) 6 (1.2–31.1); p = 0.04), and 4.2 times less likely to have infection, as compared to Ins/Ins carriers (OR  4.2, 95% CI (1.1–16); p = 0.04). Carriers of Del allele were 9.2 times more likely to develop grade 3 and 4 leukopenia, p = 0.02, 95% CI (1.1–75.6). Significant association was found between 28 bp VNTR and thrombocytopenia; (OR  3.3, 95% CI (1.1–10), p = 0.04). No significant association was found between TYMS rs2790 A > G genetic polymorphisms and MTX hematologic toxicities.

Conclusion

Genetic polymorphism of TYMS1494del6 may modulate susceptibility to MTX toxicity.

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Funding

This research was sponsored by unconditional grant provided by the Deanship of Academic Research/University of Jordan. Research sponsors neither interfered with the conductance of research, nor or in the manner data were handles or the decision to publish.

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Authors and Affiliations

  1. Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Queen Rania Street, Amman, 11942, Jordan

    Abrar Al-Sheikh, Al-Motassem Yousef, Daniah Alshamaseen & Rand Farhad

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  1. Abrar Al-Sheikh
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  2. Al-Motassem Yousef
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  3. Daniah Alshamaseen
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  4. Rand Farhad
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Corresponding author

Correspondence to Al-Motassem Yousef.

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All authors declare that they have no conflict of interest.

Ethical approval

The protocol of the study was approved by the institutional review board (IRB) of Royal Medical Services (IRB no. 1762, 14/2/2017), and conducted in concordance with the principles of the Declaration of Helsinki 1964 and its later amendments or comparable ethical standards.

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Informed consent was obtained from all participants and their parents or legal guardians before inclusion into the study.

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Al-Sheikh, A., Yousef, AM., Alshamaseen, D. et al. Effects of thymidylate synthase polymorphisms on toxicities associated with high-dose methotrexate in childhood acute lymphoblastic leukemia. Cancer Chemother Pharmacol 87, 379–385 (2021). https://doi.org/10.1007/s00280-020-04197-8

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