GSTM1 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 M1 (GSTM1) is of interest because it possesses a present/null polymorphism where the null genotype has a complete absence of GSTM1 enzyme activity.
Gene polymorphisms of the GSTs might influence the detoxification activities of the enzymes, predisposing individuals to cancers such as gynaecological cancer, breast cancer, prostate cancer, hepatocellular carcinoma, colorectal cancer (CRC) and oral squamous-cell carcinoma. A GSTM1 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.
The GSTM1 gene is located on chromosome 1p13.3 and is expressed in various tissues. The gene consists of seven introns and eight exons which encodes a cytosolic protein of 218 amino acid residues. GSTM1 is generally considered a protective enzyme because it detoxifies several toxic and carcinogenic substances such as nitrosamines and polycyclic aromatic hydrocarbons (PAHs), including diol epoxides of benzo[a]pyrene (BPDE).
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 GSTM1 deletion, they are thought to be at an increased risk of malignancies because of their reduced capacity to detoxify potential carcinogens.
Variation in prostate cancer incidence among different racial groups and geographic locations has been well documented. In 2015, Cao et al. set out to determine the role of the GSTM1 deletion polymorphism on prostate cancer risk in men of Asian descent. The analysis of 1 098 cases and 1 588 controls revealed a significantly increased prostate cancer risk among subjects carrying the GSTM1-null genotype. Stratified analysis according to country revealed significant associations for men from China and Korea, but not from Japan. A prior 2013 meta-analysis from Liu et al., reportedly being the first to investigate the GSTM1-null genotype and prostate cancer susceptibility particularly in Asians, agreed with these results. The inclusion of 18 studies (2 046 cases and 2 876 controls) also revealed a significant association within the Asian population, whilst possession of a dual null genotype for GSTM1 and GSTT1 posed a particularly higher risk.
The abovementioned was reiterated in a meta-analysis from Gong et al. (2012): subjects with dual null genotypes for GSTM1 and GSTT1 were at increased risk for developing prostate cancer. Data from 44 case-control studies comprising 7 893 prostate cancer cases and 9 668 controls showed that the individuals who carried the GSTM1 null genotype had a significantly increased prostate cancer risk compared with those who carried the GSTM1 present genotype in all subjects. When stratified by ethnicity, the same elevated risks were found in Caucasians and Asians, but not in Africans.
Cai et al. (2013) considered 18 studies with a total of 7 119 subjects to establish a significant association between the GSTM1-null genotype and overall increased prostate cancer risk. This susceptibility remained significant for Caucasian and Asian populations, although it was not found in African American men.
Yu et al. (2009) conducted case-control studies that included 1920 subjects, to find that the GSTM1-null genotype confers an increased risk for breast cancer development compared with that in GSTM1-present individuals. This was subsequently confirmed by a meta-analysis of all 41 relevant studies.
A recent 2018 meta-analysis from Zhou et al. included 72 studies, which contained 20 239 cases and 24 393 controls, to assess the relationship between the GSTM1-null genotype and bladder cancer susceptibility. The authors found that the GSTM1-null genotype was associated with bladder cancer risk in the overall population, and individually in Caucasians, Africans and Asians. Similarly, a 2017 meta-analysis from Yu et al. reported the GSTM1-null genotype associated with an increased risk for bladder cancer after the analysis of 46 studies (12 751 cases and 15 519 controls). Subgroup analyses indicated that the GSTM1 deletion was associated with an increased risk of bladder cancer in Caucasians and Asians, in both smokers and non-smokers.
To investigate the association between the GSTM1-null genotype and gastric cancer, Meng et al. (2014) considered 47 case-control studies (6 678 cases and 12 912 controls). After pooling available data from all included studies, the authors found that there was a significant association between this polymorphism and overall gastric cancer risk (in the world population), which is in line with reports from Saadat et al. and Boccia et al. Within the subgroup analysis according to ethnicity, significant association of the GSTM1-null genotype with gastric cancer risk was detected in an Asian population, but not in Caucasians, which is in line with a previous meta-analysis conducted by Qiu et al. (Meng et al. 2012)
Yang et al. (2015) aimed to clarify the association of the GSTM1 deletion polymorphism with lung cancer risk in the Chinese population. Overall, the authors observed an association, which remained significant in both smokers and non-smokers when stratified according to smoking status. Considering that cigarette smoking is an evident risk factor for lung cancer, and that GSTM1 is involved in the metabolism of various carcinogens present in cigarette smoking, a subgroup analysis regarding smoking status was conducted. This meta-analysis, based on 53 studies including 7 833 cases and 10 353 controls, supported the results from two previous meta-analyses that also reported an association of the GSTM1-null genotype with increased lung cancer risk in Chinese population(s).
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.
Liu et al. (2014) analysed 26 studies (3 769 cases and 5 517 controls) to determine if there was any association between the GSTM1-null genotype and hepatocellular carcinoma in China and India. A significant association was seen in the Chinese population, although with subgroup analyses, the authors concluded that there was no significant association between the GSTM1-null genotype and hepatocellular carcinoma in the Indian population and the Chinese population studies published in English.
Increase the Intake of Cruciferous Vegetables
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.
One hypothesis is that individuals with the null genotype of the GSTM1 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) 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 high intake of isothiocyanates among homozygous GSTM1 and GSTT1 null allele carriers vs. no risk reduction among wildtype allele carriers. These results could indicate that isothiocyanates 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 GSTM1-null genotype, but studies in the United States show the opposite relationship or no relationship.
Limit Red Meat Intake
In a prospective study of the American population by the National Institutes of Health (NIH) including around 0.5 million people, it was confirmed that more frequent red meat consumption increases the risk of CRC; however, this relationship was stronger for rectal cancer than for colon cancer. A meta-analysis of 22 studies from around the world showed a strong positive relationship between red meat consumption more than once a day and cancer of both the colon and rectum.
Klusek et al. (2019) aimed to investigate the influence of GST gene polymorphisms and red meat intake on CRC occurrence in the Polish population (197 patients and 104 controls; current and former smokers were excluded from the population). The food frequency questionnaire included the consumption of beef, pork, veal, mutton and venison, categorized by the method of preparation. It also included questions on processed red meat consumption in the form of cold meat, canned food, and sausages. High frequency consumption was defined as seven times a week or more. For a GSTM1 deletion, a high frequency of meat consumption increased the risk of CRC by almost more than 4 times.
Analysis of the frequency of red meat consumption in people without the GST polymorphism did not show statistically significant differences between patients and controls, which led the authors to speculate that high red meat intake in people with a normal GSTM1 enzyme function does not affect the risk of colon cancer.
The mechanism underlying the potential carcinogenicity of red meat has not been entirely confirmed, although the involvement of mainly heterocyclic amines (HAAs) as well as PAHs, which arise during the thermal processing of red meat, are implicated. In processed meat with a high content of salts, nitrates, and nitrites, there are N-nitroso compounds with mutagenic and carcinogenic potential. In addition, these compounds are endogenously formed as a result of meat digestion. A high level of heme iron in red meat is catalytically important for the formation reaction of harmful nitroso compounds during its passage through the digestive tract. Furthermore, heme iron promotes the formation of reactive oxygen species (ROS) with strong mutagenic properties. ROS exhibit cytotoxic effects and cause inflammation, which, in turn, promotes epithelial cell hyperproliferation.
Smoking is a known risk factor for bladder cancer, and the products of GSTs help detoxify the PAHs found in tobacco smoke.
In the Zhou et al. (2018) meta-analysis, for all patients and controls who smoked cigarettes, the authors found that the GSTM1-null genotype was associated with bladder cancer risk in the overall population and Asians. However, the authors did not find this relationship in Caucasians or Africans. In a previous study, García-Closas et al. conducted a meta-analysis of 28 studies and reported that the GSTM1-null genotype increased the overall risk of bladder cancer, although they found that it posed similar relative risks for both smokers and non-smokers (Zhou et al. 2018).
Limit Alcohol Intake
Mitrunen et al. (2001) reported that the effect of the GSTM1-null genotype was somewhat more pronounced among postmenopausal current alcohol users compared to those who reported not using alcohol. A 2-fold increase in the risk was seen among alcohol-using women with the GSTM1-null genotype, which is reportedly in accordance with the value found in a Korean study.
Genetic Polymorphisms of GSTM1, GSTT1, and GSTP1 with Prostate Cancer Risk: A Meta-Analysis of 57 Studies
Gong et al, 2012.