Negative prognostic value of glutathione S-transferase(GSTM1 and GSTT1) deletions in adult acute myeloid leukemia

Abstract

Glutathione S-transferases (GSTs) are enzymes involved in the detoxification of several environmental mutagens, carcinogens, and anticancer drugs. GST polymorphisms resulting in decreased enzymatic activity have been associated with several types of solid tumors. We determined the prognostic significance of the deletion of 2 GST subfamilies genes, M1 and T1, in patients with acute myeloid leukemia (AML). Using polymerase chain reactions, we analyzed the GSTM1 and GSTT1 genotype in 106 patients with AML (median age, 60.5 years; range, 19-76 years).The relevance of GSTM1 and GSTT1 homozygous deletions was studied with respect to patient characteristics, response to therapy, and survival. Homozygous deletions resulting in null genotypes at the GSTM1 and GSTT1 loci were detected in 45 (42%) and 30 (28%) patients, respectively. The double-null genotype was present in 19 patients (18%). GST deletions predicted poor response to chemotherapy (P ‫؍‬ .04) and shorter survival (P ‫؍‬ .04). The presence of at least one GST deletion proved to be an independent prognostic risk factor for response to induction treatment and overall survival in a multivariate analysis including age and karyotype (P ‫؍‬ .02). GST genotyping was of particular prognostic value in the cytogenetically defined intermediaterisk group (P ‫؍‬ .003). In conclusion, individuals with GSTM1 or GSTT1 deletions (or deletions of both) may have an enhanced resistance to chemotherapy and a shorter survival. (Blood. 2002;100: 2703-2707)

Role ofCYP2D6, CYP1A1, CYP2E1, GSTT1, andGSTM1 genes in the susceptibility to acute leukemias

“…When we examine the association between pediatric and adult patients, we found that adult ALL group showed a decrease in the frequency of GSTT1 null genotype (OR ¼ 0.2, P ¼ 0.04). Although different studies reported associations between lack of activity of the GSTT1 enzyme and risk of developing leukemia [35,37,38], our finding show different risks because of the number of samples in the adult ALL group, which was too small to support an association. We observed the GSTM1 null genotype frequencies increased in ALL (62.6%) and AML (68.1%) patient groups compared to controls (55.0%).…”

“…The homozygous CYP1A1*2A genotype frequency was decreased in our ALL patients, whereas it was increased in AML patients, but the differences were not statistically different (Tables I and II). CYP1A1 variants result in increased enzyme activity or inducibility such as *2, *3, and *4 are found associated with the leukemia development [37,38], and the risk of leukemia needs to be evaluated with the studies of these additional CYP1A1 variants.…”

Increased Risk of Acute Myeloid Leukemia in Patients with <i>CYP</i>1<i>A</i>1 Polymorphisms

“…GST polymorphisms are widely spread in the population, with a large proportion of individuals presenting with homozygous deletion of the genes. There are only a few reports on AML susceptibility and it has been postulated that CYP and GST polymorphisms resulting in decreased enzymatic activity have been associated with an increased risk of cancer, including leukemia [6][7][8]. Also, xenobiotic metabolizing enzymes polymorphisms may influence the prognosis of AML and Hodgkin's lymphoma, as previously shown [6].…”

Genetic polymorphisms in glutathione‐S‐transferase genes (GSTM1, GSTT1, GSTP1) and survival after chemotherapy for invasive breast carcinoma

“…31,32 Furthermore, single and combined deletions at both of these gene loci have been linked to enhanced drug resistance and poor clinical outcome in patients with carcinomas of the ovary 33 and the lung, 34 and also in patients with leukemia. 35,36 Some of these discrepancies may be attributable to methodologic issues, such as differences in study design, study population, sample size, and genotyping methods; differences in GST expression in target tissue; or differences in chemotherapy regimens used.…”