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Influence of genetic variants in asparaginase pathway on the susceptibility to asparaginase-related toxicity and patients' outcome in childhood acute lymphoblastic leukemia

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Abstract

Background

Asparaginase (ASNase) is a key component in the treatment protocols of childhood acute lymphoblastic leukemia (ALL). Asparagine synthetase (ASNS) and the basic region leucine zipper activating transcription factor 5 (ATF5) mediate the anti-leukemic effect of ASNase. Only a few reports studied the association between polymorphisms in these genes and treatment-related toxicity and response. Therefore, the current study aimed to investigate the association of ASNS and ATF5 polymorphisms with the susceptibility to ASNase-related toxicity and disease outcome in a population of childhood ALL Egyptian patients.

Methods

In this study, 88 children with ALL were enrolled and genotyped for ASNS T629A and ATF5 C362T polymorphisms using allelic discrimination assay.

Results

The studied polymorphisms did not associate with hypersensitivity or thrombosis, while the ATF5 C362T polymorphism was associated significantly with decreased ASNase-associated pancreatitis (AAP) risk under the dominant model. Patients carrying TT/CT genotypes of ATF5 C362T polymorphism had a significantly better overall survival (OS) and longer event-free survival (EFS) compared to patients with CC genotype. Multivariate analysis confirmed the independent prognostic value of the ATF5 C362T dominant model.

Conclusion

ATF5 362TT and CT genotypes were associated with decreased risk to develop AAP and better disease outcome demonstrating a low risk for events and superior survival.

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Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Zoology Department, Faculty of Science, Ain Shams University, Cairo, Egypt

    Yomna H. Youssef & Nefissa H. Meky

  2. Pediatrics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Sara M. Makkeyah

  3. Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt

    Ahmed F. Soliman

Authors
  1. Yomna H. Youssef
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  2. Sara M. Makkeyah
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  3. Ahmed F. Soliman
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  4. Nefissa H. Meky
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Contributions

(I) Conception: SMM, AFS, and NHM; (II) provision of study materials or patients: SMM and YHY; (III) collection and assembly of data: YHY, and AFS; (IV) preparation of the manuscript: AFS; (V) revision for important intellectual content: SMM and NHM; (VI) final approval of manuscript: all authors.

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Correspondence to Ahmed F. Soliman.

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Youssef, Y.H., Makkeyah, S.M., Soliman, A.F. et al. Influence of genetic variants in asparaginase pathway on the susceptibility to asparaginase-related toxicity and patients' outcome in childhood acute lymphoblastic leukemia. Cancer Chemother Pharmacol 88, 313–321 (2021). https://doi.org/10.1007/s00280-021-04290-6

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