GlutathioneStransferases polymorphisms are associated with increased risk of relapse in pediatric patients with acute lymphoblastic leukemia

ABBATE, MERCEDES; LEONARDI, DAIANA BEATRIZ; BRANDANI, JAVIER NAHUEL; RICCHERI, MARIA CECILIA; GUERON, GERALDINE; ALFONSO, GRACIELA; VAZQUEZ, ELBA SUSANA; COTIGNOLA, JAVIER

Chicago

Congreso; AACR Annual Meeting 2016; 2016

American Association for Cancer Research

Current treatment protocols of the International BerlinFrankfurtMünsterStudy Group (BFM) for childhood Acute LymphoblasticLeukemia (ALL) include the stratification of patients into groups of risk for disease relapse. This stratification is based onbiochemical, molecular and cytogenetic parameters at diagnosis, and the early response to treatment determined by the minimalresidual 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 areinconclusive and seem to be population specific. Hence, we aimed to analyze the predictive value of germline polymorphisms forchildhood 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: 019).The protocol was approved by the Institutional Ethical Committee in compliance with the Ethical Principles enunciated by theDeclaration of Helsinki. Genotypes were analyzed using PCRRFLP(GSTP1 c.313A>G, MDR1 c.3435T>C, and MTHFRc.665C>T) and multiplex PCR (GSTT1 null, GSTM1 null). Relapsefreesurvival (RFS) was assessed using the KaplanMeiermethod and the risk for relapse was estimated using multivariate Cox proportional hazard models (median followuptime: 52months). 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 2.6foldincreased risk for relapse (95%CI=1.16.1,p=0.030). In addition, since GSTs are enzymes that frequently participate in the same biological pathways with overlappingsubstrate 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 a2.5foldincreased risk for relapse (95%CI=1.15.6,p=0.027).GST polymorphisms seemed to modify the risk of relapse and RFS of Argentine patients with childhood ALL. The inclusion ofthese genetic markers in ALL treatment protocols might improve risk stratification and reduce the number of relapses and deaths.