Glutathione S-transferase gene polymorphic sequence variations: Association with risk and response to Imatinib among...

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.

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).

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).

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.