الفهرس 
Review of literatureOnly 14 pages are availabe for public view
Abstract
ALL constitutes 30% of all pediatric malignancies and 70% of pediatric leukemia. ASNase has become a key component in the treatment of ALL since its anti-proliferative properties on leukemic cells were first identified and characterized in the
1970s.
The ASNase treatment has been related to serious adverse effects in ALL patients including, but not limited to, hypersensitivity reactions, AAP, and cerebrovascular accidents. The polymorphisms of the genes mediating the ASNase anti-leukemic effect can underlie observed variability.
Therefore, the main goal of the present study was to assess the association of functional polymorphisms of ASNS and ATF5 genes in the ASNase pathway with the susceptibility to ASNase-related toxicity and disease outcomes in a population of childhood ALL Egyptian patients.
This was an observational prospective study that included
88 eligible children recruited from the Pediatric Oncology Clinic, Ain Shams University Children’s Hospital, Cairo, Egypt in the period between March 2014 and August 2019.
Informed consent was obtained from the legal guardians of each subject before enrolment in the study. This work was performed per the Declaration of Helsinki for experiments involving humans and the study protocol was approved by the Ethics Committee of Faculty of Medicine, Ain Shams University, Cairo, Egypt.
All subjects were subjected to
•Full history and clinical examinations including a) Demographic data.
b) Diagnosis
•Date of first complaints.
•Date of the diagnosis.
•Age at diagnosis.
•Immunophenotyping.
•Cytogenetic analysis.
•Risk stratification of each disease. c) Treatment
•Protocol of therapy.
•Phase of treatment.
•Other treatments modalities: e.g. radiotherapy.
• Therapy related adverse events: e.g., hypersensitivity, pancreatitis, or thrombotic events.
•SNPs selection in ASNS and ATF5 genes using the NCBI
dbSNP database.
• Detection of ASNS T629A and ATF5 C362T gene polymorphisms using allelic discrimination (AD) assay.
• Detection of the extent of a mutation effect on the structure and stability of the protein using I-Mutant 2.0.
The results of the study can be summarized as follows
•Patients’ age ranged between 1.2 and 15.7 years. The
majority of the patients were males, having WBCs count
<50000 cells/μl, and expressed CD10. The median value of
blast percentage in the bone marrow at diagnosis was 90%.
• One patient treated with CCG protocol showed a poor response of bone marrow after the induction phase, and another case suffered from a refractory disease, whereas 5
patients treated with the total XV protocol showed a poor response, besides, 6 patients died during the induction phase.
• Hypersensitivity, AAP, and thrombotic events were experienced with a frequency of 11.36%, 9.09%, and
6.82%, respectively.
• During a median follow-up time of 19.92 months, 2 patients were lost during the follow-up, 7 patients relapsed and 15 died, while the mean EFS and OS intervals were
57.04 months, and 63.78 months, respectively.
• The genotypic distribution of the two polymorphisms was consistent with HWE.
• Results of I-Mutant 2.0 revealed that the studied SNPs decrease the stability of their protein products.
• The ASNS T629A SNP showed a borderline significant association with decreased risk of AAP under the dominant model only after adjusting for sex and age.
• The ATF5 C362T SNP was associated significantly with decreased AAP risk under the allelic and dominant models after adjusting for sex and age.
• Concerning hypersensitivity and thrombosis, the studied SNPs failed to show any association under any of the tested models.
•When the association between ASNS T629A and ATF5
C362T polymorphisms and the clinical features of the patients was tested, the older age only (>10 years) showed a significant association with the presence of AA and TA genotypes of ASNS.
• The prognostic value of ASNS T629A and ATF5 C362T polymorphisms for childhood ALL was determined using Kaplan-Meier analysis and Log-Rank test. The results
showed that patients carrying AA/TA genotypes of the ASNS T629A SNP had a significantly better OS and a borderline significantly longer EFS compared to patients with TT genotype. The same tendency was found in ATF5
C362T SNP where patients carrying TT/CT genotypes had a significantly better OS and longer EFS compared to patients with CC genotype.
• The association of each SNP with OS and EFS of childhood ALL was assessed using Cox’s regression analyses.
1. The univariate analyses confirmed the association of ASNS T629A SNP with better OS and a borderline significant association with longer EFS under the dominant model. Further, the analyses confirmed the association of ATF5
C362T SNP with longer OS and lower risk of events under the dominant model.
2. The multivariate analysis adjusted for age, sex, WBCs count, immunophenotype, and CD10 expression was performed. For OS, the results revealed the independent prognostic value of ATF5 C362T dominant model, whereas
ASNS T629A dominant model showed a borderline significance. Regarding EFS, the dominant model of ATF5 C362T only was shown to be independent prognostic factor.
In summary, the present work reported an association between TT/CT genotypes of ATF5 C362T SNP and decreased risk to develop AAP. Further, ATF5 362TT and CT genotypes were associated with better disease outcome demonstrating a low risk for events and superior survival, whereas ASNS
629AA and TA genotypes could serve as an independent prognostic factor for OS. This information may pave the road for further pharmacogenetic studies to improve the prediction of risk both in survival and toxicity, supportive care and early interventions, and to establish personalized medicine based on individual genetic variations.