Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

Glutathione S-transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeut ic agents, some of which are suspected human carcinogens. Functional polymo rphisms exist in at least three genes that encode GSTs, including GSTM1, GS TT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, s pecifically to therapy-related acute myeloid leukemia (t-AML), a devastatin g complication of long-term cancer survival. Elucidation of genetic determi nants may help to identify individuals at increased risk of developing t-AM L. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AM L, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1. Gene de letion of GSTM1 or GSTT1 was not specifically associated with susceptibilit y to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were s ignificantly over-represented in t-AML cases compared with de novo AML case s [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11-2.94]. Moreove r, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more of ten among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39-5.09), particularly among those with prior exposure to known GSTP 1 substrates (OR, 4.34; 95% CI, 1.43-13.20), and not among those t-AML pati ents with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50-2.07) . These data suggest that inheritance of at least one Val allele at GSTP1 c odon 105 confers a significantly increased risk of developing t-AML after c ytotoxic chemotherapy, but not after radiotherapy.