Glutathione S-Transferase M1, T1, P1 Genotypes and Risk for Development of Colorectal Cancer

Abstract

The glutathione S-transferase (GST) supergene family is an important part of cellular enzyme defense against endogenous and exogenous chemicals, many of which have carcinogenic potential. The present investigation was conducted to detect a possible association between polymorphisms at the GSTM1, GSTT1, and GSTP1 genes and the interaction with cigarette smoking and colorectal cancer incidence. We examined 181 patients with colorectal cancer and 204 controls. DNA was extracted from whole blood, and the GSTM1, GSTT1, and GSTP1 polymorphisms were determined using a real-time polymerase chain reaction and fluorescence resonance energy transfer with a Light-Cycler instrument. Associations between specific genotypes and the development of colorectal cancer were examined by use of logistic regression analysis to calculate odds ratios (OR) and 95% confidence intervals (CI). The GSTM1 polymorphism was associated with an increased risk of developing colorectal cancer (OR = 1.62, 95% CI: 1.06-2.46). Also the risk of colorectal cancer associated with the GSTT1 null genotype was 1.64 (95% CI: 1.10-2.59). Statistically no differences were found between patients with colorectal cancer and control groups for the GSTP1 Ile/Ile, Ile/Val and Val/Val genotypes. In addition, the frequencies of the GSTM1 and GSTT1 deletion genotypes differed significantly between the cases and controls for current smokers; the GSTT1 null genotype especially is associated with a greater risk of colorectal cancer (OR = 2.44, 95% CI: 1.24-4.81). The GSTM1 and GSTT1 deletions were associated with an increased risk of developing a transverse or rectal tumor (OR = 1.86, 95% CI: 1.15-3.00; OR = 1.70, 95% CI: 1.02-2.84; respectively). The glutathione S-transferase polymorphisms were not associated with risk in patients stratified by age. The risk of colorectal cancer increased as putative high-risk genotypes increased for the combined genotypes of GSTM1 null, GSTT1 null, and either GSTP1 valine heterozygosity or GSTP1 valine homozygosity (OR = 2.69, 95% CI: 1.02-7.11). In conclusion, the results obtained in this study clearly suggest that those susceptibility factors related to different GST polymorphic enzymes are predisposing for colorectal cancer.

The GSTP1 Ile105Val Polymorphism is not Associated with Susceptibility to Colorectal Cancer

“…This suggests the mutant allele is randomly distributed in cancer and control cases. Our results are in harmony with the findings of many other reports, who found no effect of the genotype for GSTP1 on colorectal cancer susceptibility (Welfare et al, 1999;Loktionov et al, 2001;Seow et al, 2002;Ates et al, 2005;Sun et al, 2005). Furthermore, they found that the frequencies for the Val-105 allele were 0.33 for controls, and 0.31 for cases, which are almost similar to that of the present study 0.29 and 0.27 for controls and cancer cases respectively (Welfare et al, 1999).…”

“…GSTP1 has a polymorphic site at codon 105 (exon 5), where an A to G transition causes an Ile to Val substitution (Ile105Val), resulting in lower enzyme activity to variety of electrophilic molecules (Millar et al, 1999;Hayes et al, 2005;McIlwain et al, 2006). Numerous reports assessed the risk of colorectal cancer development in subjects carrying the variant Val GSTP1 allele; however, the results are controversial (Harries et al, 1997;Welfare et al, 1999;Kiyohara, 2000;Grubben et al, 2001;Loktionov et al, 2001;Seow et al, 2002;Ates et al, 2005;Sun et al, 2005).…”

“…Therefore, it is reasonable to speculate that a carcinogen metabolizing enzymes with lower activity could be associated with an elevated risk of developing cancer. However, to date, the potential association between genetic polymorphism of GSTP1 and colorectal carcinoma is somehow still controversial and may vary from population to population (Welfare et al, 1999;Ates et al, 2005;Vlaykova et al, 2007;Epplein et al, 2009;Matakova et al, 2009;Hlavata et al, 2010;Sameer et al, 2012).…”

“…There is also considerable data on the role of oxidative stress in relation to colorectal cancer risk (Yoshida et al, 2007). Furthermore, it has been suggested that up to 80% of human cancers arise as a consequence of environmental exposure (Ates et al, 2005;Dang et al, 2005). Enzymes involved in the detoxification of carcinogenic compounds as well as DNA repair may play a role in the susceptibility to colorectal cancer and other forms of cancer (Vlaykova et al, 2007;Zhang et al, 2007).…”

Predictive Role of GSTs on the Prognosis of Breast Cancer Patients with Neoadjuvant Chemotherapy

“…Genotyping for GSTM1, GSTT1 and GSTP1 polymorphisms by PCR-RFLP assay was done following a modified method of Ateş et al (Ateş et al, 2005). The primer sequences of GSTM1, GSTT1 and GSTP1 polymorphisms were 5'-GAACTCCCTGAAAAGCTAAGC-3' (forward) and 5'-GTTGGGGCTCAAATATACGGTGG-3' (reverse), 5'-TTCCTTACTGGTCCTCACATCTC-3' (forward) and 5'-TCACCGGATCAGGCCAGCA-3' (reverse), and 5'-ACCCCAGGGCTCTATGGGAA-3' (forward) and 5'-TGAGGGCACAAGAAGCCCCT-3' (reverse), respectively.…”