Abstract
Introduction Glutathione S-transferase (GST) gene deletion or polymorphic sequence variations lead to decreased enzyme activity that influences susceptibility and response to tyrosine kinase inhibitors in chronic myeloid leukemia (CML). We aimed to analyze relation of different GST gene sequence variants with susceptibility and response to Imatinib in CML.
Material and Methods A total of 150 CML cases and equal number of age and gender matched healthy controls were genotyped for five GST polymorphisms by multiplex-PCR and PCR-RFLP techniques. BCR-ABL1 transcripts were quantified by quantitative Real Time PCR (qRT-PCR).
Results GSTT1, GSTO1, and GSTO2 SNPs revealed no association, while as GSTM1(null) genotype was observed to protect against the development of CML (OR = 0.53, P = .01). GSTP1 variant genotypes AG (OR = 2.1, P = .003) and GG (OR = 5.6, P < .001), significantly associated with increased risk of CML. Combined genotype analysis showed protective impact of GSTT1(present)/GSTM1(null) (OR = 0.44, P = .003) while as GSTT1(present)/GSTP1-GG (OR = 6.92, P < .001) and GSTM1(present)/GSTP1-GG (OR = 6.33, P < .001), significantly increased CML risk. GSTM1(null) genotype individually and in combination with GSTT1(present) associated with superior rate of major molecular response (MMR) and event free survival (EFS) (log-rank P = .029). GSTO2-AG+GG genotype associated with significantly inferior MMR rates at 3, 6, and 12 months. Also, patients with GSTO2-GG genotype showed significantly reduced EFS (log-rank P = .025). Multivariate analysis confirmed GSTM1(null) as a better (HR:0.19, P = .029) and GSTO2-GG genotype as an independent poor prognostic factor (HR:2.29, P = .037).
Conclusion GSTM1(null) genotype seems to have a better prognostic role while GSTP1 variants significantly increase CML risk. Also, results support a correlation between disease outcome and GSTO2 polymorphism.