GSTT1 Research Articles

Pharmacogenetic assessment of cytostatic therapy efficacy depending on the polymorphism of T1 and M1 glutathione-S-transferase genes in breast cancer patients

Aim. To study the effect of deletion polymorphism of the GST genes (GSTT1, GSTM1) on chemotherapy (CT) efficacy in women diagnosed with breast cancer (BC) in the Primorsky Krai. Materials and methods. The study involved 132 women with breast cancer aged 23 to 79 years (mean age 48 ± 13 years) who received chemotherapy treatment. The detection of deletion (null) genotypes of GSTM1 and GSTT1 was carried out using multiplex PCR followed by an analysis of the melting curves of the reaction products. Results. Relapse-free survival (RFS) of BC patients with the “null” GSTT1 genotype was statistically significantly higher (116.7 months (9.6 years) versus 75.8 months (6.2 years)) than in patients with the “normal” GSTT genotype. Thus, in the case of the GSTT1“null” genotype, the risk of disease relapse decreased by 2.4 times (HR = 0.418, CI = 0.191–0.915, p = 0.024). Similar to GSTT1, the DFS of patients with the GSTM1 null genotype increased from 72.7 months (6 years) to 76.1 months (6.3 years). At the same time, the risk of disease relapse in carriers of the “null” GSTM1 genotype decreased by 1.7 times (HR = 0.596, CI = 0.369–0.964, p = 0.033) compared with that in carriers of the “normal” GSTM1 genotype. Conclusions. Deletion polymorphism of the GSTT1 and GSTM1 genes has a significant impact on chemotherapy efficacy in breast cancer patients. Carriers of “null” genotypes demonstrated a higher RFS and a lower risk of developing disease relapse. Further research in this direction and validation of the data obtained may contribute to individualizing the treatment of breast cancer patients, optimizing chemotherapy regimens, and reducing the number of adverse events.

Associations of GST Gene Polymorphisms and GST Enzyme Activity with the Development of Noise-Induced Hearing Loss in Chinese Han Males

Introduction: In noise-induced hearing loss (NIHL), glutathione S-transferases (GSTs) play a pivotal role as antioxidants in cochlear protection. Nevertheless, the variability in population and environmental factors complicates the interpretation of research findings on the association among GST gene polymorphism, GST enzyme activity, and NIHL, leading to inconsistent results. To explore the potential correlation between them, we took a cross-sectional survey. Methods: For workers with NIHL, standard 1:1 propensity score matching was applied to create a highly comparable control group. Multiplex PCR was used to detect GSTT1 and GSTM1 gene deletions, PCR-restriction fragment length polymorphism was used to detect the GSTP1 rs1695 gene polymorphism, and a GST assay kit was used to measure total plasma GST activity. Furthermore, we analyzed the relationship among GST gene polymorphism, GST enzyme activity, and NIHL. Results: This study included 144 workers with NIHL and 144 workers with normal hearing. The GSTM1 null genotype was significantly higher among workers with NIHL than controls (64.6% vs. 49.3%), regression analysis revealed a significant correlation between GSTM1 null genotype and elevated susceptibility to NIHL (p = 0.013). Workers with NIHL had significantly lower GST activity than healthy controls (p < 0.05). GST enzymes were not affected by GSTT1, GSTM1, or GSTP1 polymorphisms. Conclusion: GSTM1 null genotype but not GSTM1 alone may confer susceptibility to NIHL, and serum GST enzyme activity is linked to NIHL.

The moderation effect of GSTM1/GSTT1 gene polymorphisms on the association of sperm mitochondrial DNA copy number and sperm mobility

Oxidative stress (OS) is believed to be a significant factor in the decline of semen quality, with mitochondrial DNA copy number (mtDNAcn) serving as a sensitive biomarker for both semen quality and mitochondrial dysfunction resulting from oxidative stress. While glutathione S-transferases (GSTs) are commonly known as ‘antioxidant’ enzymes, there is ongoing debate regarding the relationship between GST genotypes and semen quality. In a study involving 568 male volunteers from the outpatient department of Puyang Reproductive Medicine Center, sperm mtDNAcn, semen quality, and GSTM1/GSTT1 genotypes were analyzed to investigate the potential link between GSTM1/GSTT1 gene variations and semen quality, as well as the impact of GSTs gene variations on the connection between sperm mtDNAcn and semen quality. Adjusting for variables such as age, BMI, smoking, and alcohol consumption, it was found that mtDNAcn was significantly correlated with decreased sperm concentration and total sperm count (b = − 0.109, − 0.128, respectively; P = 0.002, 0.001, respectively). GSTM1 was associated with progressive motility (OR 0.390, 95% CI 0.218, 0.697), Straight line velocity (VSL) (OR = 0.606, 95% CI 0.385, 0.953), and Straightness (STR) (OR 0.604, 95% CI 0.367, 0.994), while GSTT1 was linked to progressive motility (OR 0.554, 95% CI 0.324, 0.944) and Beat crossover frequency (OR 0.624, 95% CI 0.397, 0.982). The GSTT1 was found to moderate the relationship between mtDNAcn and sperm motility parameters linearity (LIN), STR, and Wobble (WOB), with additive interaction effects observed between GSTT1 and mtDNAcn on LIN, STR, and WOB (P for interaction = 0.008, 0.034, 0.010, respectively). Overall, this study suggests that GSTT1 and GSTM1 gene variations may play a role in sperm motility, with GSTT1 potentially influencing the impact of oxidative stress on sperm motility.

Influence of Genetic Polymorphisms on the Age at Cancer Diagnosis in a Homogenous Lynch Syndrome Cohort of Individuals Carrying the MLH1:c.1528C>T South African Founder Variant.

Background: High variability in the age at cancer diagnosis in Lynch syndrome (LS) patients is widely observed, even among relatives with the same germline pathogenic variant (PV) in the mismatch repair (MMR) genes. Genetic polymorphisms and lifestyle factors are thought to contribute to this variability. We investigated the influence of previously reported genetic polymorphisms on the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. Methods: A total of 359 LS variant heterozygotes (LSVH) from 60 different families were genotyped for specific genetic polymorphisms in GSTM1, GSTT1, CYP1A1, CYP17, PPP2R2B, KIF20A, TGFB1, XRCC5, TNF, BCL2, CHFR, CDC25C, ATM, TTC28, CDC25C, HFE, and hTERT genes using Multiplex Polymerase Chain Reaction and MassArray methods. Kaplan-Meier survival analysis, univariate and multivariate Cox proportional hazards gamma shared frailty models adjusted for sex were used to estimate the association between age at cancer diagnosis and polymorphism genotypes. A p-value < 0.05 after correcting for multiple testing using the Benjamini-Hochberg method was considered significant at a 95% confidence interval. Results: We identified three genotypes in the cell-cycle regulation, DNA repair, and xenobiotic-metabolism genes significantly associated with age at cancer diagnosis in this cohort. The CYP1A1 rs4646903 risk (GG) and CDC25C rs3734166 polymorphic (GA+AA) genotypes were significantly associated with an increased risk of a younger age at cancer diagnosis (Adj HR: 2.03 [1.01-4.08], p = 0.034 and Adj HR: 1.53 [1.09-2.14], p = 0.015, respectively). LSVH who were heterozygous for the XRCC5 rs1051685 SNP showed significant protection against younger age at cancer diagnosis (Adj HR: 0.69 [CI, 0.48-0.99], p = 0.043). The risk of a younger age at any cancer diagnosis was significantly high in LS carriers of one to two risk genotypes (Adj HR: 1.49 [CI: 1.06-2.09], corrected p = 0.030), while having one to two protective genotypes significantly reduced the risk of developing any cancer and CRC at a younger age (Adj HR: 0.52 [CI: 0.37-0.73], and Adj HR: 0.51 [CI: 0.36-0.74], both corrected p < 0.001). Conclusions: Polymorphism genotypes in the cell-cycle regulation, DNA repair, and xenobiotic metabolizing genes may influence the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene.

Absence of the GSTT1 gene in a recipient can cause anti-GSTT1 non-HLA antibody development contributing to AMR

Absence of the GSTT1 gene in a recipient can cause anti-GSTT1 non-HLA antibody development contributing to AMR

Null polymorphism of the GSTM1 and GSTT1 genes in susceptibility to colorectal tumorigenesis: systematic review with meta-analysis

Objective: To assess if GSTT1 and GSTM1 null polymorphisms increase susceptibility to colorectal cancer. Methods: A search was conducted in PubMed, SciELO, BVS, and Medline databases. Forty articles were selected, totaling 12,698 cases and 19,517 controls. Odds ratios with 95% confidence intervals were used, and p-values &lt;0.05 were considered significant. The Dersimonian-Laird method was applied for p-values &lt;0.05, and the Mantel-Haenszel method was used otherwise. All p-values were two-tailed with an alpha value of 0.05 determined a priori. STATA 16.0 software was utilized. Result: A higher risk of colorectal cancer was shown in the general population for the GSTM1 null genotype (OR=1.11; 95%CI [1.03, 1.19]; P&lt;0.01). No significant risk was observed for GSTT1 or the GSTM1/GSTT1 null combination (OR=1.09; 95%CI [0.98, 1.22]; P&lt;0.01 and OR=1.13; 95%CI [0.89, 1.43]; P&lt;0.01, respectively). In subgroup analysis, increased colorectal cancer risk was found for Asians with the GSTM1 null genotype (OR=1.10; 95%CI [1.02, 1.20]; P=0.02) and GSTM1/GSTT1 null combination (OR=1.49; 95%CI [1.03, 2.15]; P&lt;0.01). Conclusion: The findings suggest that the GSTM1 null polymorphism and the GSTM1/GSTT1 null combination are potential susceptibility factors for colorectal cancer, particularly in the Asian population.

Associations of polymorphisms of glutathione-S-transferase and N-acetyltransferase 2 genes in children with acute lymphoblastic leukemia

The development of personalized medicine is inextricably linked with the study of the patient’s genetic profile, which determines not only the features of the course of the disease, but also the risks of its occurrence. Purpose. The aim of the work was to study possible associations between the genetic polymorphisms GSTT1, GSTM1, NAT2 and predisposition to the development of acute lymphoblastic leukemia in children of the East Siberian region. Material and methods. A total of 82 children with acute lymphoblastic leukemia and 227 healthy volunteers with no history of hematological pathology were examined. Deletion polymorphisms in the glutathione S-transferase GSTT1 and GSTM1 genes were detected by polymerase chain reaction (PCR) with electrophoretic detection of amplification products in agarose gel; the type of acetylation was determined by genotyping SNP rs1495741 of the NAT2 gene by conducting a polymerase chain reaction in real time. The material for the study was DNA samples isolated from buccal epithelium samples. Results. Statistical processing allowed us to draw the following conclusions: the rate of acetylation of xenobiotics does not affect the risk of acute lymphoblastic leukemia in children of the Caucasian ethnic group of the East Siberian region. Conclusion. There is no associative relationship between deletions in the GSTM1 and GSTT1 genes and the risk of developing acute lymphoblastic leukemia in children of the Caucasian ethnic group of the East Siberian region. It was found that the risk of developing acute lymphoblastic leukemia in children was significantly higher with the variant of combinations of alleles of the rapid type of NAT2 acetylation and normal activity of GSST1 and GSTM1 (G/G, active, active).

Glutathione-S-Transferase Theta 2 (GSTT2) Modulates the Response to Bacillus Calmette-Guérin Immunotherapy in Bladder Cancer Patients.

Glutathione-S-transferases (GST) enzymes detoxify xenobiotics and are implicated in response to anticancer therapy. This study evaluated the association of GST theta 1 (GSTT1), GSTT2, and GSTT2B with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) response in non-muscle-invasive bladder cancer treatment. In vitro assessments of GSTT2 knockout (KO) effects were performed using cell lines and dendritic cells (DCs) from GSTT2KO mice. Deletion of GSTT2B, GSTT1, and single-nucleotide polymorphisms in the promoter region of GSTT2 was analysed in patients (n = 205) and healthy controls (n = 150). Silencing GSTT2 expression in MGH cells (GSTT2BFL/FL) resulted in increased BCG survival (p < 0.05) and decreased cellular reactive oxygen species. In our population, there are 24.2% with GSTT2BDel/Del and 24.5% with GSTT2BFL/FL. With ≤ 8 instillations of BCG therapy (n = 51), 12.5% of GSTT2BDel/Del and 53.8% of GSTT2BFL/FL patients had a recurrence (p = 0.041). With ≥9 instillations (n = 153), the disease recurred in 45.5% of GSTT2BDel/Del and 50% of GSTT2BFL/FL. GSTT2FL/FL patients had an increased likelihood of recurrence post-BCG therapy (HR 5.5 [1.87-16.69] p < 0.002). DCs from GSTT2KO mice produced three-fold more IL6 than wild-type DCs, indicating a robust inflammatory response. To summarise, GSTT2BDel/Del patients respond better to less BCG therapy and could be candidates for a reduced surveillance regimen.

Glutathione S-transferase theta 1 (GSTT1) deletion polymorphism and susceptibility to head and neck carcinoma: a systematic review with five analyses

Glutathione S-transferase theta 1 (GSTT1) enzyme plays a key role in the neutralization of electrophilic compounds such as carcinogens. Herein, we aimed to evaluate GSTT1 deletion polymorphism and susceptibility to head and neck carcinoma (HNC) according to 107 articles in a systematic review with five analyses. The databases of PubMed/Medline, Web of Science, Scopus, and Cochrane Library from the beginning of each database until June 21, 2023, with no restrictions to identify pertinent articles. The RevMan 5.3 software was used to calculate the effect sizes, which were displayed as the odds ratio (OR) along with a 95% confidence interval (CI). Both the publication bias and sensitivity analyses were performed using the CMA 3.0 software. A trial sequential analysis (TSA) was conducted. Of the 1966 records retrieved from four databases, 107 articles were included in the analysis. The combined analysis revealed that the pooled OR was 1.28 (95% CI: 1.14 to 1.44; p-value < 0.0001). The pooled OR was highest in mixed ethnicity. Nasopharyngeal cancer had the highest OR (1.84), followed by oral cancer (OR = 1.20), and laryngeal cancer (OR = 1.17). Studies with less than 200 samples had a higher OR compared to those with 200 or more samples. The studies with a quality score of 7 or more had a higher OR compared to those with a score of less than 7. When both age and sex are considered, while the OR of 1.42 is significant, the high heterogeneity suggests caution in interpreting these results. There is no evidence of publication bias. TSA reported that the study does not have sufficient statistical power. This comprehensive meta-analysis revealed a significant association between the GSTT1 null genotype and an increased risk of HNC, with variations based on factors such as ethnicity, cancer type, sample size, control source, and quality score.

Association of mRNA expression and polymorphism of antioxidant glutathione-S-transferase (GSTM1 and GSTT1) genes with the risk of Gestational Diabetes Mellitus (GDM)

Gestational Diabetes Mellitus (GDM) is a medical complication during the gestational period in which woman who had never been diagnosed with diabetes develops hyperglycemia. Prior studies have demonstrated that the advancement of GDM and its consequences arises from a disparity between oxidants and antioxidants in the cells. The observed outcomes can be attributed to an excessive formation of reactive oxygen species (ROS) within the cells, coupled with a reduced activity of anti-oxidative enzymes. Glutathione S-transferase (GSTs) is recognized as an antioxidant enzyme that is belong to as a phase II family member of detoxifying enzymes. These metabolic multigene catalysts are found into the cytoplasm of the cell. GSTs play a vital part in the elimination of cellular ROS or free radicals. The study involves total 300 pregnant women, (150 GDM cases and 150 healthy controls). The polymorphism study of GSTs genes (GSTM1 and GSTT1) was determined by conventional Polymerase Chain Reaction (PCR). The mRNA expression study of GSTM1 and GSTT1 genes analysed by qPCR/ RT-PCR (quantitative PCR/Real-Time PCR) followed by statistical analysis done using Prism8 software (version 8.01). The study revealed statistically significant variations in biochemical parameters between GDM cases and controls. It was found GSTM1-null (GSTM1-/-) polymorphism significantly (P < 0.0001) most prevalent in GDM cases (56.7%) when compared to healthy control (28%). However, no significant difference was observed for GSTT1 null and present polymorphism (P = 0.906). The gene expression levels of both GSTM1 and GSTT1 were found considerably downregulated in individuals with GDM as compared to the control group (P < 0.0001). The downregulation of gene expression has a significant (P<0.0001) association with the null/deletion polymorphism of both GSTM1/ GSTT1 genes respectively. Null/deletion genotype of GSTM1 gene and its expression showed significant association with GDM. Therefore, this gene variant has the potential to be used as a prognostic biomarker for GDM. However, there is need to study this gene variant in larger sample size and different ethnicity.

Genetic Polymorphisms in Glutathione S-Transferase (GST) Gene and Their Correlation with Toxicity of Chemotherapy in Breast Cancer Patients.

Glutathione S-Transferase (GST) is a family of phase II metabolizing enzymes contribute to detoxification and elimination of variety of endogenous as well as exogenous xenobiotics including chemotherapeutic agents. The comprehensive knowledge on the impact of genetic polymorphisms in GST) enzyme coding gene will help to understand the clinical outcomes in breast cancer patients treated with either Adriamycin or paclitaxel or combination of both. In this study we attempted to assess the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and their association with Adriamycin and Paclitaxel induced toxicity reactions in breast cancer patients. Two hundred BC patients receiving Adriamycin and Paclitaxel chemotherapy were enrolled in this study and chemotherapy induced hematological and non-hematological toxicity reactions were noted. The polymorphisms in GSTM1, GSTP1 and GSTT1 gene were studied by PCR and RFLP analysis. After the univariate analysis of the genetic polymorphisms of GSTM1, GSTP1 and GSTT1 showed that GSTT1 null genotype showed significant association with neutropenia (OR=2.84, 95% CI: 1.06-7.56; p=0.036) in breast cancer patients treated with Adriamycin and GSTT1 null genotype in patients with >1 CINV toxicity confirmed significant correlation (OR=3.75, 95% CI: 1.46-9.59; p=0.005). The genetic polymorphisms of GSTP1 (exon 5) A/G heterozygous genotype was significant in grade >1 toxicity reactions of mucositis (OR=3.22, 95% CI: 1.06-9.71; p=0.037) in breast cancer patients administered with Paclitaxel chemotherapy. The findings obtained from this study proposed significant involvement of GSTT1-null genotype in hematological neutropenia toxicity in response to Adriamycin and GSTM1-null genotype showed negative association with non-hematological toxicity (bodyache) in response to Paclitaxel.

Association of CYP3A4, GSTT1 and GSTM1 Gene Polymorphisms in early prediction of Gastritis in Choleric Temperament as per Unani Philosophy in Indian population

Association of CYP3A4, GSTT1 and GSTM1 Gene Polymorphisms in early prediction of Gastritis in Choleric Temperament as per Unani Philosophy in Indian population

Abstract B006: GSTT2 modulates immune activation and impacts response to BCG immunotherapy in bladder cancer

Abstract Whilst M. bovis Bacillus Calmette-Guérin (BCG) therapy is the gold-standard for treating high risk non-muscle invasive bladder cancer (NMIBC), 30-40% of patients fail therapy, resulting in disease recurrence and progression. Loss of glutathione-S-transferase theta 2 (GSTT2) expression resulting from a promoter deletion, has been associated with modulation of intracellular ROS and BCG survival in BC cells. Retrospective analysis of NMIBC patients revealed that patients with the promoter deletion responded better to fewer instillations of BCG. To understand these responses, wildtype (WT) and GSTT2-knockout (KO) mice were implanted with MB49-PSA BC cells, either subcutaneously or orthotopically, and treated with weekly BCG instillations. Subcutaneous tumors were harvested after 3 BCG instillations for flow cytometry analysis, or after 4 BCG instillations for immunofluorescence (IF) imaging and gene expression analysis. Bladders (orthotopic model) were harvested after 4 BCG instillations for single-cell RNA sequencing. Splenocytes from WT and KO male mice were also stimulated in-vitro with TLR agonists, for 48h, to assess immune responses. In the subcutaneous model, in male mice, the cure rate was higher in WT mice (57%) compared to KO mice (0%). Flow cytometry analysis showed significantly higher numbers of tumor-associated CD8+ T-cells in BCG-treated KO males compared to WT males; however, IF imaging revealed higher penetration of CD8+ T-cells in tumors from WT males. In female mice, the cure rate was similar in WT (25%) and GSTT2-KO (38%) mice. IF imaging showed higher penetration of CD8+ T-cells in KO females. Quantitative real-time PCR (q-PCR) analysis of BCG-treated subcutaneous tumors from female mice revealed lower expression of the immune exhaustion markers, PD-L1 and CTLA-4, in KO mice compared to WT mice. Similarly, in the orthotopic model (female mice), q-PCR analysis of bladders also showed lower expression of PD-L1 and CTLA-4 in KO mice compared to WT mice. Single-cell RNA sequencing of bladders from BCG-treated mice revealed differences in the expression of genes such as Peak1, Hmga2, Scl2a1, Kras, Ahank, Gsta4, Mecom and Sh3gl2, of which Gsta4, Mecom, Sh3gl2, Hmga2 and Peak1 were validated using q-PCR. In-vitro analysis of splenocytes from male mice revealed higher levels of IL-6, IL-1β and IFN-α, after stimulation with TLR7/8 and TLR9 agonists, in KO splenocytes relative to WT splenocytes. Despite the higher levels of cytokine production by splenocytes and higher proportion of tumor-associated CD8+ T-cells in KO male mice, these mice fared poorly, which could be explained by immune exhaustion or lack of immune penetration into the tumor. In females, lower expression of immune exhaustion markers in KO mice did not yield better responses; however, single-cell data showed differences in expression of genes associated with pro- and anti-tumorigenic pathways, which could influence response. Thus, loss of GSTT2 may influence the response to BCG therapy, through modulating downstream signaling pathways and immune responses. Citation Format: Mugdha Vijay Patwardhan, Kane Toh, Edmund Chiong, Ratha Mahendran. GSTT2 modulates immune activation and impacts response to BCG immunotherapy in bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B006.

Genetic association of the xenobiotic biotransformation system with the risk of death of the gestational sac in primigravida women living in an industrial city

Introduction. Every second conception in the population ends in failure, in 20% of the cases the cause is a non-developing pregnancy. In the overall structure of early reproductive losses, missed miscarriage accounts for 80%. The development of this pathology is influenced by both endogenous and exogenous factors. Exogenous factors with a teratogenic effect lead to the occurrence of mutations and the formation of an abnormal embryo, which is poorly predicted. The peculiarities of the biotransformation system of xenobiotics of the maternal organism directly affect the severity of the impact of these factors on the embryo. Materials and methods. A survey of eighty six young primigravida women living in Novokuznetsk was conducted. 33 of them were diagnosed with the gestational sac death, 53 women had a standard developed pregnancy. Variants of the GSTM1 and GSTT1 genes of the second phase of the xenobiotic biotransformation system were determined in these groups by polymerase chain reaction. Results. Novokuznetsk, a city with a critically high level of environmental pollution, has recorded a 20–fold increase in the number of missed miscarriages over the past 25 years. A statistically reliable association of deletion polymorphisms of the genes of the second phase of the xenobiotic biotransformation system with the death of the gestational sac - GSTM1 (χ2 – 5.37; OR – 3.18) and GSTT1 (χ2 – 10.85; OR – 16.64) was revealed, while the normal alleles were associated with a successful outcome of pregnancy - GSTM1 (χ2 – 5.37; OR – 0.13) and GSTT1 (χ2 – 10.85; OR – 0.06). Limitations. The study was of a pilot nature, so it is advisable to increase the sample in the future. Conclusion. The dependence between the activity of enzymes of the second phase of the xenobiotic biotransformation system and the increased risk of miscarriage of the first pregnancy in young women living in the conditions of ecological distress was revealed. The results of the study make it possible to predict possible pregnancy complications and elaborate algorithms for full-fledged pregravid preparation.

Can pharmacogenetics impact the therapeutic effect of cytarabine and anthracyclines in adult acute myeloid leukaemia patients?: A Serbian experience.

Cytarabine-anthracycline-based induction chemotherapy remains the standard of care for remission induction among patients with newly diagnosed acute myeloid leukaemia (AML). There are remarkable differences in therapy response among AML patients. This fact could be partly explained by the patients' genetic variability related to the metabolic paths of cytarabine and anthracyclines. This study aims to evaluate the effect of variants in pharmacogenes SLC29A1, DCK, ABCB1, GSTM1, and GSTT1, as well as laboratory and AML-related parameters on clinical outcomes in adult AML patients. A total of 100 AML patients were included in the study. Pharmacogenetic variants SLC29A1 rs9394992, DCK rs12648166, ABCB1 rs2032582, and GSTM1 and GSTT1 gene deletions were detected by methodology based on PCR, fragment analysis and direct sequencing. The methods of descriptive and analytic statistics were used. Survival analysis was done using the Kaplan-Meier method using the Log-Rank test. This is the first study of adult AML pharmacogenetics in the Serbian population. Clinical outcomes in our cohort of AML patients were not impacted by analysed variants in SLC29A1, DCK, ABCB1 and GSTT1, and GSTM1 genes, independently or in combinations. Achievement of complete remission was identified as an independent prognostic indicator of clinical outcome. The population-specific genomic profile has to be considered in pharmacogenetics. Since the data on AML pharmacogenetics in European populations is limited, our results contribute to knowledge in this field and strongly indicate that a high-throughput approach must be applied to find particular pharmacogenetic markers of AML in the European population.

Exposure to heavy metals, antioxidant status, and the interaction of single nucleotide polymorphisms in the genes CAT rs7943316, GSTP1 rs1695, as well as GSTM1 and GSTT1 genes, among workers in occupational settings

Individuals working in diverse fields are consistently exposed to work-related pollutants that can impact their overall health. The current study investigated the presence of pollutants in seven different occupational groups and their impact on human health. Biochemical and genetic approaches were employed. Heavy metals were determined by ICP-MS technique. Oxidative stress biochemical markers and molecular analysis of the glutathione transferases gene SNPs (GSTT1, GSTM1, GSTP1), catalase (CAT, rs7943316), and superoxide dismutase (SOD, rs17880487) was carried out. The results revealed a significantly higher quantity of Cd among five occupational groups. Catalase, malonaldehyde, and glutathione was significantly dysregulated. Molecular analysis of the gene SNPs suggests a probable relationship between the antioxidants and the phenotypic expression of the CAT, GSTP1, GSTT1, and GSTM1 SNPs. It is concluded that chronic exposure to occupational contaminants like Cd affects human health through oxidative stress in association with some of their gene SNPs.

Genetic variations in CYP2A6, CYP2E1, GSTM1, GSTT1 genes and the risk of Nasopharyngeal carcinoma in North African population.

Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy associated with both genetic and environmental factors. Polymorphic deletions of the phase I and phase II genes involved in the detoxification of potential carcinogens may be a risk factor for nasopharyngeal carcinoma. In this study, we investigated the relationship between CYP2E1 (rs3813867), CYP2A6, GSTM1(rs1183423000) and GSTT1(rs1601993659) gene variations and NPC risk in North African countries with the highest incidence of NPC (Morocco, Algeria and Tunisia). and the evaluation of the potential use of these variants as potential biomarkers for NPC management. A total of 600 NPC cases and 545 controls frequency-matched on ethnicity, sex, age and childhood household type, were recruited from three North African countries (Morocco, Algeria and Tunisia) and analysed. Genotyping of CYP2A6 and CYP2E1(rs3813867) was performed by polymerase chain reaction restriction (PCR)-fragment length polymorphism (RFLP) analysis and the GSTM1 (rs1183423000) and GSTT1(rs1601993659) genetic variations were evaluated using the PCR technique. The genotype distributions of CYP2E1(rs3813867), CYP2A6, GSTM1(rs1183423000) and GSTT1(rs1601993659) genotypes did not differ significantly among NPC cases and controls (p>0.05). Furthermore, our data did not reveal any association with smoking and the studied variants, even when the samples were stratified by the duration period of smoking. In this large studied North African population, our findings suggest that the functional CYP2E1, CYP2A6, GSTM1 and GSTT1 variations did not influence NPC susceptibility.

Abstract P29: GSTT2 AND THE RESPONSE TO BCG IMMUNOTHERAPY

Abstract Whilst M. bovis Bacillus Calmette-Guérin (BCG) therapy remains the gold-standard for treatment of high-risk non-muscle invasive bladder cancer (BC), 30-40% of patients fail therapy, resulting in disease recurrence and progression. A better understanding of the underlying mechanisms of BCG therapy can aid in revealing key response pathways, which may lead to the discovery of new targets, and in turn new approaches to treat BC. The glutathione-S-transferase theta 2 (GSTT2) gene is a member of the GST family. Loss of GSTT2 expression has been associated with modulation of intracellular ROS and BCG survival in BC cell lines. Retrospective analysis of BC patients revealed that patients with the GSTT2B deletion responded better to fewer instillations of BCG. To understand these responses, wild-type (WT) and GSTT2-knockout (KO) mice were implanted with MB49-PSA BC cells, in subcutaneous and orthotopic settings. Once tumors were established, the mice were treated with four weekly BCG instillations, after which the subcutaneous tumors and bladders were harvested for downstream analysis. Single-cell RNA sequencing of whole-bladders was used to identify specific cell clusters within the bladder, and to analyze differential gene expression. Hmga2, Ahnak and Peak1 were found to be differentially expressed in bladders from WT and GSTT2-KO mice. These genes are known to be involved in pro- and anti-tumorigenic pathways such as epithelial-mesenchymal transition and inflammation. Additionally, quantitative real-time PCR analysis in the subcutaneous and orthotopic tumors revealed differences in the expression of immune-related genes, especially markers of immune exhaustion such as PD-L1 and CTLA-4. Flow cytometry analysis of subcutaneous tumors also revealed differences in T-cell infiltration. Thus, loss of GSTT2 may influence the response to BCG therapy, through modulating downstream signaling pathways and immune responses. Elucidating such pathways can lead to a better understanding of the mechanism of BCG and its role as a therapy for BC. Citation Format: Mugdha Patwardhan, Kane Toh, Edmund Chiong, Ratha Mahendran. GSTT2 AND THE RESPONSE TO BCG IMMUNOTHERAPY [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P29.

The Role of Glutathione in Age-Related Macular Degeneration (AMD).

Age-related macular degeneration (AMD) is a chronic disease that usually develops in older people. Pathogenetic changes in this disease include anatomical and functional complexes. Harmful factors damage the retina and macula. These changes may lead to partial or total loss of vision. The disease can occur in two clinical forms: dry (the progression is slow and gentle) and exudative (wet-progression is acute and severe), which usually starts in the dry form; however, the coexistence of both forms is possible. The etiology of AMD is not fully understood, and the precise mechanisms of the development of this illness are still unknown. Extensive genetic studies have shown that AMD is a multi-factorial disease and that genetic determinants, along with external and internal environmental and metabolic-functional factors, are important risk factors. This article reviews the role of glutathione (GSH) enzymes engaged in maintaining the reduced form and polymorphism in glutathione S-transferase theta-1 (GSTT1) and glutathione S-transferase mu-1 (GSTM1) in the development of AMD. We only chose papers that confirmed the influence of the parameters on the development of AMD. Because GSH is the most important antioxidant in the eye, it is important to know the influence of the enzymes and genetic background to ensure an optimal level of glutathione concentration. Numerous studies have been conducted on how the glutathione system works till today. This paper presents the current state of knowledge about the changes in GSH, GST, GR, and GPx in AMD. GST studies clearly show increased activity in ill people, but for GPx, the results relating to activity are not so clear. Depending on the research, the results also suggest higher and lower GPx activity in patients with AMD. The analysis of polymorphisms in GST genes confirmed that mutations lead to weaker antioxidant barriers and may contribute to the development of AMD; unfortunately, a meta-analysis and some research did not confirm that connection. Unspecific results of many of the parameters that make up the glutathione system show many unknowns. It is so important to conduct further research to understand the exact mechanism of defense functions of glutathione against oxidative stress in the human eye.

Polymorphic Loci of Xenobiotic Biotransformation Genes in Accumulated Mercury Pollution Liquidators and in Workers with Chronic Mercury Vapors Exposure.

The allele and genotype frequencies of the polymorphic loci CYP1A1 (rs1048943), GSTP1 (rs1695 and rs1138272), GSTM1, and GSTT1 genes were studied in 517 men: in 389 accumulated mercury pollution liquidators (207 firefighters of the Ministry of the Russian Federation for Civil Defence, Emergencies and Elimination of Consequences of Natural Disasters and 182 employees of the Federal Environmental Operator) and 128 former workers (82 patients in the delayed period of chronic mercury intoxication and 46 individuals contacted with mercury and had no chronic mercury intoxication). We found differences in the frequencies of AA and AG genotypes in groups of former workers (χ2=6.96, p=0.008) for the polymorphic locus rs1048943, while the AG-CYP1A1 genotype was characterized by a 5.5-fold decrease in the odds ratio for the development of chronic mercury intoxication (OR=0.18, p=0.0041). An unfavorable combination of genotypes of the studied polymorphic loci increases the risk of undesirable health effects.