Glutathione S-transferase polymorphisms in children with myeloid leukemia:A children's cancer group study

GSTM1 and GSTT1 are polymorphic genes. Absence of enzyme activity is due to homozygous inherited deletion of the gene, reducing detoxification of carc inogens such as epoxides and alkylating agents and potentially increasing c ancer risk. We hypothesized that GST null genotype would increase risk of a cute myeloid leukemia and myelodysplasia (AML/MDS) in children. DNA was ext racted from bone marrow slides of 292 AML/MDS patients, PCR amplification w as used to assign GSTM1 and GSTT1 genotypes for cases and controls. Given t hat the frequency of the null genotype varies by ethnicity and that the maj ority of the cases were Caucasian, analyses were restricted to 232 white (n on-Hispanic) cases and 153 Caucasian non cancer controls, The frequency of GSTM1 null was significantly increased in AML/MDS cases compared with contr ols {64 versus 47%; odds ratio (OR), 2.0 [95% confidence interval (CT), 1.3 -3.1]; P = 0.001), whereas the frequency of GSTT1 null genotype in AML/MDS cases was not statistically different from controls. AML comprises biologic ally distinct subtypes, and a test for homogeneity revealed a statistically significant difference among subtypes (P = 0.04; df, 8) for GSTM1 only, In particular, there was an increased frequency of GSTM1 null genotypes in Fr ench-American-British groups M3 [82%; n = 22; OR, 5.1 (95% CI, 1.6-21.3)] a nd M4 [72%; n = 53; OR, 2.9 (95% CI, 1.4-6.0)]. We conclude that the GSTM1 null genotype is a significant risk factor for childhood AML, particularly French-American-British groups M3 and M4. This may indicate an important ro le for exogenous carcinogens in the etiology of childhood AML.