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

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.