Glutathione S-transferases (GSTT1 and GSTM1) gene deletions in Tunisians: susceptibility and prognostic implications in breast carcinoma

Abstract

Glutathione S-transferase Theta1 and Mu1 (GSTT1 and GSTM1) are involved in the metabolism and detoxification of a wide range of potential environmental carcinogens. Conversely, they contribute to tumour cell survival by detoxification of numerous products induced by cancer therapy. The authors designed a large study to investigate the susceptibility and prognostic implications of the GSTT1 and GSTM1 gene deletions in breast carcinoma. The authors used the polymerase chain reaction to characterise the variation of the GSTT1 and GSTM1 genes in 309 unrelated Tunisian patients with breast carcinoma and 242 healthy control subjects. Associations of the clinic-pathologic parameters and the genetic markers with the rates of the breast carcinoma specific overall survival (OVS) and the disease-free survival (DFS) were assessed using univariate and multivariate analyses. A significant association was found between gene deletion of GSTT1 and the risk of early onset of breast carcinoma (OR ¼ 1.60, P ¼ 0.02). The lack of GSTT1 gene deletion was significantly associated with poor clinical response to chemotherapy (OR ¼ 2.29, P ¼ 0.03). This association was significantly higher in patients with axillary's lymph node-negative breast carcinoma (OR ¼ 12.60, P ¼ 0.005). The null-GSTT1 genotype showed a significant association with increased DFS in this selected population of patients. This association was even higher in patients carrying both null-GSTT1 and -GSTM1 genotypes. The gene deletion of GSTs may predict not only the early onset of breast carcinoma but also the clinical response to chemotherapy and the recurrence-free survival for patients with lymph nodenegative breast carcinoma.

Prospective Case–Control Study to Evaluate the Role of Glutathione S Transferases (GSTT1 and GSTM1) Gene Deletion in Breast Carcinoma and Its Prognostic Significance

“…Khedhaier et al have found a significant association between gene deletion of GSTT1 and the risk of early onset of breast carcinoma [10]. Garcia et al [22] reported no association between null genotype of both GSTT1 and GSTM1 and breast carcinoma, with null GSTT1 being protective in pre-menopausal women.…”

“…These enzymes are induced in the presence of oxidative stress [10]. Chemotherapy and radiotherapy exert their effects by generating reactive oxygen species (ROS) and their by-products [17].…”

“…Literature is lacking in studies that highlight the prognostic significance of these polymorphisms. Khedhaier et al had found a significant association between lack of GSTT1 deletion and poor response to chemotherapy [10]. The present study was done with the aim to identify the role of GSTT1 and GSTM1 genes polymorphism in the risk of development of breast cancer, and whether this polymorphism has any prognostic significance and any role in predicting the response to chemotherapy.…”

“…DNA isolation using standard salting out method was done. DNA was subjected to amplification by polymerase chain reaction (PCR) to look for the presence or absence of null genotype using primer pair [10]. GSTM1-and GSTT1-specific primer pairs were used in separate set of reaction along with β-integrin serving as an internal control.…”

“…The GSTs are induced under conditions of oxidative stress, with the α, μ, π, and θ classes especially active in the detoxification of numerous agents that cause reactive oxidant damage, protecting cells from a wide variety of environmental carcinogens [10].…”