Improving risk stratification of patients with childhood acute lymphoblastic leukemia: Glutathione-S-Transferases polymorphisms are associated with increased risk of relapse.

// Daiana B. Leonardi 1, * , Mercedes Abbate 1, * , Maria C. Riccheri 2 , Myriam Nunez 3 , Graciela Alfonso 4 , Geraldine Gueron 1 , Adriana De Siervi 5 , Elba Vazquez 1 , Javier Cotignola 1 1 Laboratorio de Inflamacion y Cancer, Departamento de Quimica Biologica, Facultad de Ciencias Exactas y Naturales-Universidad de Buenos Aires, IQUIBICEN-CONICET, Intendente Guiraldes 2160 (1428), CABA, Argentina 2 Departamento de Hematologia Pediatrica, Hospital Nacional Profesor A. Posadas, Pte. Illia s/n (1684), El Palomar, Buenos Aires, Argentina 3 Departamento de Matematicas, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Junin 954 (1113), CABA, Argentina 4 Departamento de Hematologia, Hospital Nacional Profesor A. Posadas, Pte. Illia s/n (1684), El Palomar, Buenos Aires, Argentina 5 Current Affiliation: Laboratorio de Oncologia Molecular y Nuevos Blancos Terapeuticos, Instituto de Biologia y Medicina Experimental (IBYME–CONICET), Vuelta de Obligado 2490 (1428), CABA, Argentina * These authors contributed equally to this work Correspondence to: Javier Cotignola, email: jcotignola@qb.fcen.uba.ar Keywords: acute leukemia, Glutathione-S-Transferase, polymorphism, predictor, relapse Received: October 23, 2015      Accepted: March 10, 2016      Published: April 06, 2016 ABSTRACT The inclusion of genotype at Acute Lymphoblastic Leukemia (ALL) diagnosis as a genetic predictor of disease outcome is under constant study. However, results are inconclusive and seem to be population specific. We analyzed the predictive value of germline polymorphisms for childhood ALL relapse and survival. We retrospectively recruited 140 Argentine patients with de novo ALL. Genotypes were analyzed using PCR-RFLP ( GSTP1 c.313A > G, MDR1 c.3435T > C, and MTHFR c.665C > T) and multiplex PCR ( GSTT1 null, GSTM1 null). Patients with the GSTP1 c.313GG genotype had an increased risk for relapse in univariate (OR = 2.65, 95% CI = 1.03–6.82, p = 0.04) and multivariate (OR = 3.22, 95% CI = 1.17–8.83, p = 0.02) models. The combined genotype slightly increased risk for relapse in the univariate (OR = 2.82, 95% CI = 1.09–7.32, p = 0.03) and multivariate (OR = 2.98, 95% CI = 1.14–7.79, p = 0.03) models for patients with 2/3-risk-genotypes ( GSTT1 null, GSTM1 null, GSTP1 c.313GG). The Recurrence-Free Survival (RFS) was shorter for GSTP1 c.313GG ( p = 0.025) and 2/3-risk-genotypes ( p = 0.021). GST polymorphisms increased the risk of relapse and RFS of 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.