Glutathione S-Transferase T1
The prevalence of the GSTT1-null genotype has been reported in various ethnic groups as 16% (English), 12% (German), 38% (Nigerian), and 32% (West Indian). Studies among selected groups of the Chinese and Korean populations have found null genotype frequencies of 64% and 60%, respectively. The findings of Seow et al. (1998) among adult Chinese subjects (52%) confirm previous observations that east Asian populations possess relatively high GSTT1-null genotype frequencies, compared with other population groups.
GSTT1 Gene Detail
Glutathione S-transferases (GSTs) are phase II metabolizing enzymes that play a key role in protecting against cancer by detoxifying numerous potentially cytotoxic or genotoxic compounds. Among the GST isoforms, glutathione S-transferase θ1 (GSTT1) has a present/null polymorphism where the null genotype is associated with a loss of GSTT1 enzyme activity.
The gene polymorphisms of GSTs might influence the detoxification activities of the enzymes, predisposing individuals to cancers such as oral squamous-cell carcinoma, gynaecological cancer, breast cancer, prostate cancer, hepatocellular carcinoma, and colorectal cancer. A GSTT1 homozygous deletion is associated with key enzyme deficiency, reduced detoxification function, increased susceptibility to cytogenetic damage, and thus increased risk of cancer.
Glutathione S-transferases (GSTs), a superfamily of multifunctional enzymes that include, amongst others, the glutathione S-transferase μ1 (GSTM1), θ1 (GSTT1) and π1 (GSTP1) classes, play an important role in the detoxification of various toxic compounds such as xenobiotics, environmental pollutants and pesticides, chemotherapeutic drugs, chemical carcinogens and products of oxidative stress (i.e. α, β-unsaturated aldehydes, quinones, epoxides, and hydroperoxides). These are important phase II detoxifying enzymes that catalyse the conjugation of reduced glutathione (GSH), and convert hydrophobic, electrophilic xenobiotic substances to hydrophilic metabolites. Furthermore, recent evidence has shown that GSTs modulate the signalling pathways of cell proliferation, cell differentiation, and apoptosis.
Since GSTs are essential for phase II enzymatic detoxification and protect against cellular oxidative stress and exogenous chemicals, and because they are involved in and modulate various signalling pathways, including the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, variabilities in normal GST function might play particularly vital roles in slowly developing cancers.
The GSTT1 gene, located on chromosome 22q11.23, is reportedly expressed in human erythrocytes and various other tissues including the liver. The GSTT1 enzyme is said to catalyse the detoxification of ethylene oxide and methyl bromide, as well as other halogenated metabolites.
A deletion in this gene, called a null variant allele or null genotype, results in the absence of enzyme activity. If an individual is homozygous for a GSTT1 deletion, they are thought to be at an increased risk of malignancies because of their reduced capacity to detoxify potential carcinogens.
A 2013 systematic review and meta-analysis from Liu et al., reportedly being the first to investigate the GSTT1-null genotype and prostate cancer susceptibility particularly in Asians, found a significant association. The inclusion of 15 studies (1 677 cases and 2 431 controls) revealed a significantly increased risk of prostate cancer within the Asian population. The possession of a dual null genotype for GSTM1 and GSTT1 posed a particularly higher risk in the same population.
In 2014, Zhou et al. determined that the GSTT1 null genotype was distinctly associated with prostate cancer risk in Caucasians, but not in the overall population (9 752 cases and 10 530 controls). The authors mentioned though that no subgroup analyses were performed in Asian, African or African American populations due to the small number of studies and limited data sets included in the meta-analysis.
A meta-analysis from Gong et al. in 2012 also found that subjects with a dual null genotype for GSTM1 and GSTT1 were at increased risk for developing prostate cancer. Data from 37 studies comprising 7 187 prostate cancer cases and 8 761 controls however, indicated no association between the single GSTT1-null genotype and prostate cancer risk. This is reportedly consistent with the result of many former meta-analyses.
An association between GSTT1 polymorphism and breast cancer was first reported by Bailey and co-workers in 1998 in Caucasian and African American women, after which many studies analysed the influence of GSTT1 polymorphism on breast cancer risk with no clear consensus. After reviewing 13 individual case-control studies (including 3 387 breast cancer cases and 5 085 controls) on GSTT1 gene polymorphism and breast cancer risk in the Chinese population, Xiao et al. (2005) found the GSTT1-null genotype significantly associated with an increased risk of breast carcinoma in Chinese individuals.
A previous meta-analysis from Sergentanis et al. (2009) reported on the association of the GSTT1-null genotype and increased breast cancer risk, only in non-Chinese populations. This analysis included 41 case-control studies with 16 589 breast cancer cases and 19 995 controls. Xiao et al. (2005) noted that the results of their meta-analysis were inconsistent with previously published meta-analyses, such as the abovementioned analysis, which either indicated the significant associations in Caucasians, in non-Chinese populations, or no significant associations.
A recent 2018 meta-analysis from Zhou et al. (2018) included 61 studies, which contained 13 041 cases and 16 739 controls, to assess the relationship between the GSTT1-null genotype and bladder cancer susceptibility. The authors found that the GSTT1-null genotype was significantly associated with bladder cancer risk in the overall population, but not in whites, Africans and Asians, nor in individuals who smoked cigarettes. The authors also identified an increased risk for bladder cancer in the overall population and Asians when a dual null genotype for GSTM1 and GSTT1 were present.
A 2017 meta-analysis from Yu et al. reported the GSTT1-null genotype associated with an increased risk for bladder cancer after the analysis of 54 studies (11 817 cases and 14 805 controls). Subgroup analyses indicated that the GSTT1 deletion was associated with an increased risk of bladder cancer only in Caucasians, with no association detected according to smoking status. This study also showed that non-smokers with GSTM1/ GSTT1 double-null genotypes had an elevated bladder cancer risk.
A very recent comprehensive review synopsis from meta-analysis and genome-wide association studies demonstrated strong evidence of association between the GSTT1-null genotype and gastric cancer risk.
Renal Cell Carcinoma
The susceptibility to renal cell carcinoma (RCC) has been investigated within several studies. A meta-analysis from Yang et al. (2013) found that none of the three GSTs genotypes (GSTM1, GSTT1 and GSTP1) had a significant association with the risk of RCC. These results were reportedly consistent with most of the previous studies.
Cruciferous vegetables (Brassicaceae family) contain a variety of phytochemicals (such as vitamin C, carotenoids and flavonoids), many of which are thought to play a role in cancer protection. Isothiocyanates (ITCs), the metabolites of glucosinolates (which naturally occur in cruciferous vegetables), have been shown to exert cancer-protective effects through the inhibition of phase I enzymes and the enhancement of phase II enzymes, thus blocking chemical carcinogenesis. It has also been thought to inhibit angiogenesis, induce apoptosis, inhibit pro-inflammatory reactions by repressing NFκB, and arrest cell cycle progression. Cruciferous vegetables represent the primary source of ITC exposure in humans.
Seow et al. (1998) suggested that the expression of GSTT1 is induced by dietary ITCs found in cruciferous vegetables such as cauliflower, broccoli, watercress and other Chinese varieties such as choi sum and kai choi. The authors found a strong and statistically significant association between the dietary intake of cruciferous vegetables and the urinary excretion of total ITC in Chinese subjects: urinary excretion of ITC was significantly higher among GSTT1-positive subjects when compared to GSTT1-null subjects.
Results from a more recent systematic review and meta-analysis indicated a statistically significant inverse association between cruciferous vegetable intake and colon cancer. Broccoli particularly exhibited protective benefits against colorectal cancer (CRC) / neoplasms; this is thought to be due to the higher concentration of glucosinolates found in broccoli, exposing the individual to higher levels of ITC and therefore may provide greater anticarcinogenic benefits. Interestingly, one serving of broccoli can contain up to 60 mg of glucoraphanin, a type of glucosinolate, whereas broccoli sprouts contain about 20–100 times more glucoraphanin than a full-grown broccoli head.
Stratification by GST genotype in the abovementioned analysis revealed that the GSTT1–null genotype confers a reduction in CRC risk. One hypothesis is that individuals with the null genotype of the GSTT1 polymorphism would less readily conjugate and excrete ITCs, and hence would experience a greater protective effect against neoplasm development. In their systematic review, Andersen et al. (2013) also noted that in the prospective population-based Singapore Chinese Health Study including 231 incident CRC cases and 1 194 controls, a risk reduction of 69% was found by a high intake of ITCs among homozygous GSTM1 and GSTT1 null allele carriers vs. no risk reduction among wildtype allele (GSTT1-present) carriers. These results could indicate that ITCs from cruciferous vegetables protect against CRC in individuals with low GST activity.
Epidemiologic studies in Asia and Europe show that the chemo-preventive association of cruciferous vegetable intake is more pronounced among individuals with the GSTT1-null genotype, but studies in the United States show the opposite relationship or no relationship.
GSTT1 Polymorphism and the Risk of Developing Prostate Cancer
Zhou et al, 2014.