Polymorphisms of glutathione S‐transferase mu1 (GSTM1) and theta 1 (GSTT1) genes in chronic myeloid leukaemia

To the Editor: The environmental exposure to cytotoxic and genotoxic agents, particularly those derived from benzene, may be associated with an increased risk of chronic myeloid leukaemia (CML) (1). The enzymes of the glutathione S-transferase (GST) system reduce molecules of chemical agents to less toxic levels. Gene codings for the GST mu1 (GSTM1) and theta 1 (GSTT1) proteins are polymorphic in humans and are homozygous null in approximately 50% and 20% of normal individuals, respectively, which results in a lack of the active proteins (2). An increase in homozygous GSTT1 null genotype was observed in CML patients from India (3). As GSTT1 is involved in the metabolism of ethylene oxide (EO), a genotoxic agent capable of producing heritable translocations and the frequency of spontaneous chromosome abnormalities, presumably because of EO, is higher in GSTT1 null individuals (4), it was hypothesised that the loss of the GSTT1 genes might influence the production of Philadelphia (Ph) chromosome, leading to CML. Cancer is the second most common cause of death in south-eastern Brazil and chemical agentsrelated diseases are a serious health problem in this area of the country (5, 6). For this reason, the identification of the GSTM1 and GSTT1 gene polymorphisms in CML patients, from an area in which there is a potential exposure to cytotoxic and genotoxic agents, was considered necessary in order to test whether homozygous null genotypes influenced the risk for disease. Genomic DNA obtained from bone marrow samples of 125 CML patients [73 male, 52 female; age (mean ± SD) 39.0 ± 16.4 yr; 108 White people, 17 African–Americans] and peripheral blood of 341 racially matched controls [198 male, 143 female; age (mean ± SD) 53.0 ± 4.3 yr; 296 White people, 45 African–Americans] was analysed using the multiplex-polymerase chain reaction (7, 8). The diagnosis of CML was based on haematological, cytogenetic and molecular analyses. The statistical significance of the differences between groups was calculated by chi-square or Fischer’s exact test. Crude odds ratio (OR) was given within 95% confidence intervals (CI) and was ageand gender-adjusted. We observed similar frequencies of GSTM1, GSTT1 and combined null genotypes in patients and controls (43.2% vs. 43.7%, P 1⁄4 1.00; 18.4% vs. 17.6%, P 1⁄4 0.95; and 7.2% vs. 7.9%, P 1⁄4 0.75 respectively). Individuals with GSTM1 (OR 1⁄4 0.98; 95% CI: 0.65–1.50), GSTT1 (OR 1⁄4 1.06; 95% CI: 0.62–1.80) and combined null genotypes (OR 1⁄4 0.84; 95% CI: 0.36–1.96) were at similar risk of CML compared with those without the null genotypes. We also examined the frequency of the polymorphisms in patients in relation to clinical variables (Table 1). Similar frequencies of the GSTM1, GSTT1 and combined null genotypes in patients under 50 yr or older, gender and ethnic origin were seen. The frequency of the GSTM1 null genotype was lower in patients in the accelerated phase or with blast crisis than those seen in patients with chronic phase (20.0% vs. 49.0%, P 1⁄4 0.01). Similar frequency of the GSTT1 and combined null genotypes was found in patients with distinct phases of the disease. In conclusion, our results indicate that the inherited absence of this carcinogen detoxification pathway could be unimportant for the Ph chromosome production and aetiology of CML. However, the role of the GSTM1 null genotype in different phases of this disease requires confirmation by large-scale molecular epidemiological studies.