RESUMO
BACKGROUND: Polymorphisms in the drug-metabolizing enzymes are found to be associated with the inter-individual variation in response to a particular drug. Glutathione S-transferases (GSTs) are involved in the metabolism of several anticancer drugs, including alkylating agents, anthracyclines, and cyclophosphamides. AIM: The present study is aimed to examine the association of GST and CYP1A1*2A polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) and the prognostic significance. MATERIALS AND METHODS: A total of 92 immunophenotyped patients and 150 cord blood controls were genotyped by PCR for GSTM1 and GSTT1, RQ-PCR allelic discrimination assay for GSTP1 and PCR-RFLP for CYP1A1*2A polymorphism. RESULTS: We have previously reported the significant association of GSTM1 (null) and combined GSTP1 {(Ile/Val)/ (Val/Val)} /GSTM1 (null) genotype with the susceptibility to ALL. No significant association was observed with GSTT1 (P=0.75) and CYP1A1*2A (P=0.61 for +/- and P=0.86 for -/- respectively) in the susceptibility to ALL. Survival analysis was performed in 50 of the 92 patients who were followed for three years. Kaplan-Meier survival analysis for three years showed significant lower event-free survival in patients harboring GSTP1 (Ile/Val) and GSTP1 (Val/Val) (P=0.038 and 0.0001, respectively) genotype. Cox regression analysis revealed GSTP1 as an independent prognostic marker with 6-fold higher risk with Val/Val genotype (P=0.003). CONCLUSIONS: Our results show that GSTP1 (Ile/Val) polymorphism has a role in the susceptibility to ALL and also influence treatment outcome.
RESUMO
Acute lymphoblastic leukaemia (ALL) is the most common pediatric malignancy worldwide. The origin of this disease may be explained by a combination of genetic and environmental factors. Glutathione-s-transferases are a multi-gene family of enzymes involved in the detoxification of a wide variety of environmental carcinogens. A total of 92 immunophenotyped cases (below 25 years of age) and 150 cord blood controls were here analysed by PCR for GSTM1(Present/Null) and RQ-PCR allelic discrimination assay for GSTP1(Ile105Val). We found a significant increased risk for ALL with the GSTM1 null genotype (OR: 1.96, 95%CI=1.08-3.57), but no significant risk was found with the GSTP1 (Ile/Val) genotype (OR: 1.32, 95%CI = 0.74-2.37) and the GSTP1 Val/Val genotype (OR: 1.41, 95%CI=0.5-3.96) alone. Combined analysis of GSTM1 and GSTP1 showed significant higher risk associated with the GSTM1 (null/null) and GSTP1 [(Ile/Val)/ (Val/Val)] genotype (OR=2.78: 95%CI=1.16-6.69).
