Glutathione S-Transferase Polymorphisms and Colorectal Cancer: A HuGE Review

Abstract

The genes glutathione S-transferase M1 (GSTM1) (chromosome 1p13.3) and glutathione S-transferase T1 (GSTT1) (22q11.2) code for cytosolic enzymes glutathione S-transferase (GST)-mu and GST-theta, respectively, which are involved in phase 2 metabolism. Both genes may be deleted. There is geographic and ethnic variation in genotype frequencies for both genes. In developed countries, colorectal cancer is the second most common cancer. Colorectal cancer has been inconsistently associated with polycyclic aromatic hydrocarbons in diet and tobacco. Because GST enzymes are involved in polycyclic aromatic hydrocarbon metabolism, it has been postulated that genotype may modify colorectal cancer risk associated with polycyclic aromatic hydrocarbon exposure. No consistent associations between GSTM1 or GSTT1 genotype and colorectal cancer have been observed. However, most studies have methodological limitations. Few have investigated gene-environment interactions. No interactions between GSTM1 or GSTT1 genotype and smoking and colorectal cancer risk have been reported. One polyp study suggests an interaction between GSTM1 genotype and smoking. Two studies suggest increased disease risk in subjects with high meat intake and GST nonnull genotype, contrary to the underlying hypothesis. One study suggests a strong inverse relation between colorectal adenomas and broccoli consumption, particularly in subjects who are GSTM1 null. These finding require confirmation. Methods for determining GSTM1 and GSTT1 genotype are well established. Population testing is not currently justified.

Glucosinolates inBrassicavegetables: The influence of the food supply chain on intake, bioavailability and human health

“…The two GST isoforms GST M1 and GST T1 are subjects to genetic polymorphisms, and geographic as well as ethnic variations in genotype frequencies are known for both genes. Indeed, GSTl polymorphism has been implicated as a variable, which determines the protective effect of broccoli against the development of precancerous adenomatous polyps in human populations [208]. In a recent epidemiological study, Lin et al [209] observed a protective effect of broccoli consumption against adenomatous polyps only in subjects with the GSTM1 null genotype because ITCs are conjugated and excreted more slowly in subjects who do not express GSTl, so that exposure of target tissues to the protective compound and/or metabolite is higher and prolonged.…”

Reporting, Appraising, and Integrating Data on Genotype Prevalence and Gene-Disease Associations

“…A recurrent problem in case-control studies of gene disease associations with unrelated controls has been that the controls were not selected from the same source population as the cases (10,(34)(35)(36). The potential problem of selecting controls who do not represent the population from which cases arise is illustrated by the divergence in odds ratios for the association between colorectal cancer and the glutathione S-transferase T1 gene (GSTT1) null genotype (37), when the different control groups were analyzed (36).…”

“…The potential problem of selecting controls who do not represent the population from which cases arise is illustrated by the divergence in odds ratios for the association between colorectal cancer and the glutathione S-transferase T1 gene (GSTT1) null genotype (37), when the different control groups were analyzed (36). Thus, sufficient information should be presented to assess whether controls would have become cases if they had developed the disease.…”

Covariates and confounding in epidemiologic studies using metabolic gene polymorphisms

“…However, a measure of relevant exposures is not always performed. A recent review of GSTM and GSTT polymorphisms and colorectal cancer 14 reported on 9 studies, 5 of which had no exposure assessment.…”