Polymorphisms in the glutathione S-transferase mu cluster are associated with tumour progression and patient outcome in colorectal cancer

Abstract

Glutathione S-transferase (GST) enzymes catalyse the detoxification of by-products of reactive oxygen species and are thus important in cellular defence mechanisms. The GSTs are polymorphic with allelic variants encoding isoforms with functional differences. GST polymorphism has been associated with susceptibility and clinical outcome in patients with cancer. In this retrospective cohort, we have investigated associations between common GSTM1, GSTM3 and GSTP1 polymorphisms with factors known to influence clinical outcome and patient survival in colorectal cancer. Significant linkage disequilibrium was demonstrated between GSTM1 and GSTM3 alleles (P≤0.001). We identified no significant associations between the GSTP1 Ile105Val105 polymorphism and any clinical outcome parameters or patient survival. However significant associations were demonstrated with mu class GSTs. Those patients who were GSTM1 null presented less frequently with poorly-differentiated tumours (P=0.038). Furthermore, patients who were GSTM3 AA were less likely to present with advanced stage tumours (T-stage, P=0.036 and Dukes' classifications, P=0.012) or distant metastases (P=0.017) when examined alone. Upon further examination of the effect of linkage disequilibrium, we found that, in GSTM1 null individuals, GSTM3 AA (compared with other GSTM3 genotypes combined) had longer disease-free survival (HR=0.54, 95% CI 0.30-0.98, P=0.044). Thus, the GSTM3 AA genotype is associated with improved prognosis especially in those with GSTM1 null. Our findings suggest that the GST mu gene cluster mediates tumour characteristics and survival in patients with colorectal cancer.

GSTT1, GSTM1, and GSTP1 polymorphisms as a prognostic factor in women with breast cancer

“…In line with the present study of BC, previous investigations of Hodgkin's lymphoma, ovarian cancer, colorectal cancer, and even BC have also found the same improved survival rates when lymph node status was associated with polymorphic forms of GSTT1, GSTM1, and GSTP1 (Khedhaier et al, 2003;Huang et al, 2003;Hohaus et al, 2005;DeMichele et al, 2005;Beeghly et al, 2006;Holley et al, 2006;Kweekel et al, 2008;Kolwijck et al, 2009;Jones et al, 2009;Khrunin et al, 2010).…”

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

“…The phase II drug-metabolizing enzymes, including GST or ALDH, have also been studied in regard to personalized medication with cyclophosphamide. Several investigations of Hodgkin's lymphoma, ovarian cancer, colorectal cancer, and breast cancer have found improved survival rates associated with polymorphic forms of GSTT1, GSTM1, and GSTP1 [95][96][97][98][99][100][101][102][103] . The activity and genetic polymorphisms of GSTP1 were associated with clinical outcomes and toxicities of cyclophosphamide in Han Chinese (South China) with systemic lupus erythematosus [95] .…”

Glutathione-S-Transferases in Development, Progression and Therapy of Colorectal Cancer

“…Similarly, no effect of GSTM3 polymorphism was found in a large study investigating the role of single SNPs within 11 genes of phase I and 15 genes of phase II of xenobiotic metabolism (Landi et al, 2005). Opposite results have been reported for GSTM3*A/GSТМ3*В alleles (the latter arising from a 3 bp deletion in intron 6): patients who were carriers of genotypes with at least one GSTM3*B allele (GSTM3 AB and GSTM3 BB combined) had advanced tumour T-stage, increasing Dukes' stage, higher frequency of distant metastases and shorter survival (Holley et al, 2006) Thus, the GSTM3 AA genotype was suggested to be associated with improved prognosis of CRC especially in patients with GSTM1 null genotype (Holley et al, 2006). Analogous results have been reported by Loktionov et al who found associations between GSTM3*B frequency in patients with distal colorectal cancers particularly when combined with the GSTM1 null genotype (Loktionov et al, 2001).…”