Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Observational Study
. 2021 Mar;87(3):379-385.
doi: 10.1007/s00280-020-04197-8. Epub 2020 Nov 10.

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

Abrar Al-Sheikh  1 , Al-Motassem Yousef  2 , Daniah Alshamaseen  1 , Rand Farhad  1
Affiliations
Observational Study

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

Abrar Al-Sheikh et al. Cancer Chemother Pharmacol. 2021 Mar.

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.

Keywords: Acute lymphoblastic leukemia; Genetic polymorphisms; High-dose methotrexate; Thymidylate synthase; Toxicity.

PubMed Disclaimer

References

    1. Whitehead TP, Metayer C, Wiemels JL, Singer AW, Miller MD (2016) Childhood Leukemia and Primary Prevention. Curr Probl Pediatr Adolesc Health Care 46(10):317–352. https://doi.org/10.1016/j.cppeds.2016.08.004 - DOI - PubMed - PMC
    1. Jordan national cancer registry (2013) Cancer Incidence in Jordan. https://www.moh.gov.jo/Echobusv3.0/SystemAssets/a05a084b-3781-4979-a217-... . Accessed 20 Jun 2018
    1. Hunger SP, Mullighan CG (2015) Acute Lymphoblastic Leukemia in Children. N Engl J Med 373(16):1541–1552. https://doi.org/10.1056/NEJMra1400972 - DOI - PubMed
    1. Chu E, Drake JC, Boarman D, Baram J, Allegra CJ (1990) Mechanism of thymidylate synthase inhibition by methotrexate in human neoplastic cell lines and normal human myeloid progenitor cells. J Biol Chem 265(15):8470–8478 - DOI
    1. Mathews CK (2012) DNA synthesis as a therapeutic target: the first 65 years. Faseb J 26(6):2231–2237. https://doi.org/10.1096/fj.12-0602ufm - DOI - PubMed - PMC

Publication types

MeSH terms

LinkOut - more resources