Glutathione-S-Transferases Polymorphisms Are Associated With Increased Risk Of Relapse In Pediatric Patients With Acute Lymphoblastic Leukemia

Current treatment protocols of the International Berlin-Frankfurt-Munster Study Group (BFM) for childhood Acute Lymphoblastic Leukemia (ALL) include the stratification of patients into groups of risk for disease relapse. This stratification is based on biochemical, molecular and cytogenetic parameters at diagnosis, and the early response to treatment determined by the minimal residual disease. ALL treatment protocols are continuously revised and improved, but some patients still recur and die of disease. The inclusion of genotype at ALL diagnosis as a genetic predictor of disease outcome is under constant study. However, results are inconclusive and seem to be population specific. Hence, we aimed to analyze the predictive value of germline polymorphisms for childhood ALL relapse in order to support their inclusion as additional tools in disease diagnosis and therapeutic protocols. We retrospectively recruited 140 Argentine patients diagnosed with de novo ALL (median age at diagnosis: 6.1 years old, range: 0-19). The protocol was approved by the Institutional Ethical Committee in compliance with the Ethical Principles enunciated by the Declaration of Helsinki. Genotypes were analyzed using PCR-RFLP (GSTP1 c.313Au003eG, MDR1 c.3435Tu003eC, and MTHFR c.665Cu003eT) and multiplex PCR (GSTT1 null, GSTM1 null). Relapse-free survival (RFS) was assessed using the Kaplan-Meier method and the risk for relapse was estimated using multivariate Cox proportional hazard models (median follow-up time: 52 months). Multivariate models included gender, risk group, treatment protocol, age at diagnosis and genotypes as covariates. Patients with the GSTP1 c.313GG genotype had worse RFS (p = 0.025) and a 2.6-fold increased risk for relapse (95%CI = 1.1-6.1, p = 0.030). In addition, since GSTs are enzymes that frequently participate in the same biological pathways with overlapping substrate specificity, we considered an additive score that captures information on the genotypes of GSTT1, GSTM1 and GSTP1. We found that patients with higher number of risk alleles genotype had statistically significant shorter RFS (p = 0.021) and over a 2.5-fold increased risk for relapse (95%CI = 1.1-5.6, p = 0.027). GST polymorphisms seemed to modify the risk of relapse and RFS of Argentine patients with childhood ALL. The inclusion of these genetic markers in ALL treatment protocols might improve risk stratification and reduce the number of relapses and deaths. Citation Format: Maria M. Abbate, Daiana B. Leonardi, Javier N. Brandani, Maria C. Riccheri, Geraldine Gueron, Graciela Alfonso, Elba S. Vazquez, Javier Cotignola. Glutathione-S-transferases polymorphisms are associated with increased risk of relapse in pediatric patients with acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5021.