Polymorphisms within glutathione S-transferase genes and initial response to glucocorticoids in childhood acute lymphoblastic leukaemia

Abstract

In children with acute lymphoblastic leukaemia (ALL) treated according to protocols of the Berlin-Frankfurt-Münster (BFM) study group, the initial response to prednisone is the strongest predictor of therapy outcome. Glutathione S-transferases (GSTs) have been implicated in glucocorticoid resistance. In order to assess a potential association of phenotypically relevant GST polymorphisms with prednisone response in childhood ALL, we conducted a case-control study of 45 prednisone poor-responders (cases) and 90 prednisone good-responders (controls) who were frequency matched according to initial white blood cell count. In addition, we analysed the association of GST genotypes with relapse of leukaemia. In univariate analysis, homozygous deletion of GSTT1 (null genotype) conferred a 6.7-fold reduction in risk of prednisone poor-response compared to individuals who were either heterozygous or homozygous for GSTT1 [odds ratio (OR) = 0.15, P = 0.071; multivariate odds ratio = 0.18, P = 0.117]. GSTM1 and GSTP1 genotypes did not show any association with prednisone response. In addition, risk of relapse was predicted strongest by the GSTT1 genotype. In univariate analysis, the GSTT1 null genotype conferred a 5.9-fold reduction in risk of relapse compared to the heterozygous or homozygous presence of GSTT1 (OR = 0.17, P = 0.095; multivariate OR = 0.23; P = 0.173). No associations of the GSTM1 genotype with risk of relapse were observed. GSTP1 codon 105 and codon 114 polymorphisms were predominantely associated with central nervous system relapse. Our results add further support to the hypothesis that genetic polymorphisms within specific GST genes might be of clinical importance in childhood ALL.