Disease relevance of GSTM1

• CONCLUSIONS: A common genetic polymorphism divides the population of never smokers into two groups of approximately equal size, one (homozygous carriers of the GSTM1 null allele) that has a statistically significant greater risk of lung cancer from ETS than the other (heterozygous or homozygous carriers of the wild-type GSTM1 allele) [1].
• RESULTS: The GSTM1 homozygous null genotype was associated with an increased risk of developing breast cancer (OR = 2.10; 95% CI = 1.22-3.64), principally due to an association with postmenopausal breast cancer (OR = 2.50; 95% CI = 1.34-4.65) [2].
• ORs for pancreatic cancer among heavy smokers with both GSTT1-null and GSTM1-null genotypes were similar in magnitude to those among heavy smokers with the GSTT1-null genotype alone [3].
• Differential association of the codon 72 p53 and GSTM1 polymorphisms on histological subtype of non-small cell lung carcinoma [4].
• No influence of GSTM1, GSTT1, or GSTM3 polymorphisms was evidenced on docetaxel toxicity [5].

Psychiatry related information on GSTM1

• Of the genotypes presumed to be protective, only GSTM1 A/B influenced susceptibility; the GSTM1 A/B frequency was lower in the patients than the control individuals both before [odds ratio = 0.3, 95% confidence interval (CI) 0.1-0.7] and after correction for imbalances in age, sex, smoking and alcohol consumption (odds ratio = 0.2, 95% CI 0.1-0.5) [6].
• There was weak risk reduction associated with GSTM1 null in heavy smokers (OR = 0.71; 95%CI 0.54-0.94; P = 0.02), but neither GSTM1 nor MPO genotypes affected the overall risk of NSCLC [7].
• This protective effect mediated by the presence of GSTM1 was even more pronounced within the subset of therapy group B patients at highest clinical risk of treatment failure (B-ALL, disease stage IV, disease stage III with unresected abdominal tumor, and LDH activity > or = 500 U/L) [8].
• Moreover, GSTM1 gene deletion and missense mutation (Pro187Ser) of the NQO1 gene showed no significant association with alcohol withdrawal symptoms [9].
• In this study, we investigated a possible association between polymorphisms of the GSTM1, NQO1, and NQO2 genes and alcohol withdrawal symptoms such as delirium tremens, hallucination, and seizure [9].

High impact information on GSTM1

• Five patients developed acute hepatitis B (HB) within four months after major operations by the same obstetric-gynecologic surgeon [10].
• When considered together, no combination of the GSTM1 and GSTT1 genotypes was associated with an increased risk of breast cancer [11].
• CONCLUSIONS: Our data provide evidence against a substantially increased risk of breast cancer associated with GSTM1 and/or GSTT1 homozygous gene deletions [11].
• Glutathione S-transferase mu and theta polymorphisms and breast cancer susceptibility [11].
• The GSTM1-null and the NAT2 slow-acetylator genotypes have been associated with increased risks for the development of environmentally induced cancers [12].

Chemical compound and disease context of GSTM1

• We conclude, first, that mu class glutathione S-transferase influence risk of upper aerodigestive tract cancers thereby complementing studies in skin cancer patients showing GSTM1 A/B is protective, while GSTM3 AA moderately increases risk [6].
• We therefore performed a systematic review of 10 studies on association of endometriosis and various genes involved in dioxin detoxification process excluding GSTM1/GSTT1 [13].
• Our findings suggest that genetic polymorphisms GSTM1/T1 could modify estrogen-related breast cancer risk [14].
• Recent studies suggest an association between the EPHX1 codon 113 polymorphism or homozygous null GSTM1 allele and the risk of carcinogenesis, emphysema, phenytoin-associated oral clefting, and the risk of spontaneous abortion [15].
• Moreover, no correlation was found between the GSTM1 or GSTT1 genotype and ifosfamide toxicity and the urinary excretion of its metabolites [16].

Biological context of GSTM1

• Separately, the presence of PAH-dGMP adducts was associated with the GSTM1 null genotype (absence of the gene) (odds ratio = 8.6; 95% confidence interval = 1.03-100) [17].
• The relationship between GSTM1 and GSTT1 gene deletions and breast cancer risk was not substantially modified by cigarette smoking [11].
• With this clone, the location of the GSTM1-GSTM5 gene cluster on chromosome 1 was confirmed by fluorescence in situ hybridization [18].
• The close physical proximity of the GSTM1 and GSTM2 loci, which share 99% nucleotide sequence identity over 460 nucleotides of 3'-untranslated mRNA, suggests that the GSTM1-null allele may result from unequal crossing-over [18].
• Identification of class-mu glutathione transferase genes GSTM1-GSTM5 on human chromosome 1p13 [18].

Anatomical context of GSTM1

• To investigate a relationship between genetically determined individual predispositions and mutations of target genes in the early stage of lung carcinogenesis, we examined p53 mutations in relation to germ line polymorphisms of the CYP1A1 and GSTM1 genes, using surgical specimens of 148 non-small cell lung cancer patients who were smokers [19].
• These results imply that the GSTM1 null genotype has a weak correlation, but another 4 genetic polymorphisms are unlikely to be associated, with oral cavity cancer among Japanese [20].
• A higher proportion of the patients with positive lymph node status at the time of diagnosis had a combined GSTM1 null/GSTT1 null genotype (P = 0.05) [21].
• The relative levels of expression of GSTM1 and GSTM3 in brain cytosols were determined after resolution of these enzymes using chromatofocusing [22].
• Cells isolated from colon tissue were identified to be colonocytes and colon fibroblasts, both of which also expressed substantial levels of GSTM1 and GSTM2 [23].

Associations of GSTM1 with chemical compounds

• CYP2D6 and CYP2E1 genotypes are associated with higher 7-methyl-dGMP levels, while the GSTM1 null genotype is associated with higher numbers of PAH-dGMP adducts [17].
• CYP1A1 and GSTM1 polymorphisms affect urinary 1-hydroxypyrene levels after PAH exposure [24].
• Overall, statistically significant interactions in predicting DNA adduct levels were observed between the GSTM1-null genotype and consumption of leafy vegetables (P = 0.01), white meat (P = 0.04), and intake of vitamin C (P = 0.04), vitamin E (P = 0.05) and beta-carotene (P = 0.02) [25].
• In individuals not occupationally exposed to PAHs GSTM1 and smoking seem to influence the urinary concentration of 2-naphthol [26].
• The GSTM1 genotype was clearly the most significant parameter explaining the variance in urinary PHEMA excretion (6-fold lower in GSTM1 null subjects; P < 0.0001) so that systematic GSTM1 genotyping should be recommended routinely for a correct interpretation of PHEMA urinary levels [27].

Physical interactions of GSTM1

• Based on adjustment by age, gender and smoking history, the MPO GA interacted with the presence of GSTM1 and GSTT1 genotypes to significantly reduce the risk (OR = 0.17, 95% CI = 0.03-0.98) [28].

Enzymatic interactions of GSTM1

• Earlier clinical manifestations and death before the age of 5 years are typical for GSTM1-deleted CF patients [29].

Regulatory relationships of GSTM1

• GSTM1 deletion was quite common in both controls (49.4%) and cases (50.3%) but was not associated with risk of lung cancer alone or in combination with the MPO polymorphism [30].
• The objective of this study was to determine whether the association between GSTM1 null/GSTTI null and survival in ovarian cancer is mediated by the influence of these genes on p53 expression [31].
• In addition, hGST 5.8 expressed glutathione peroxidase activity toward phospholipid hydroperoxides and GSH-conjugating activity toward 9,10-epoxy stearic acid [32].
• GSTA1-1 inhibited the formation of adducts more than 6-fold and GSTM1-1 and GSTP1-1 about 2-fold [33].
• In this meta-analysis involving 14 GSTM1 studies with 1539 cases and 1805 controls and nine GSTT1 studies with 746 cases and 834 controls, respectively, substantial heterogeneities among studies were found [34].

Other interactions of GSTM1

• These data underline the major importance of the CYP1A1 inducibility phenotype associated with the homozygous GSTM1 null genotype in chemically induced cancers [35].
• NAT2 slow genotypes were also associated with CpG G:C-A:T (OR, 6.2; CI:0.7-52), whereas GSTM1 null was associated with non-CpG G:C-A:T (OR, 7.8; CI, 0.9-65) [36].
• The potential modifying role of previously analyzed GSTM1, GSTM3, and GSTP1 genotypes was also examined [37].
• GSTM1 AB (P = 0.016) and GSTP1 Val/Val (P = 0.046) were also associated with fewer BCC in this group [38].
• In conclusion, low or deficient activities of two conjugating enzymes of foreign compound metabolism, GSTM1 and NAT2, may influence types of acquired mutations in p53 in bladder cancer [39].

Analytical, diagnostic and therapeutic context of GSTM1

• In a nested case-control study, we investigated associations between genetic variability in specific GST genes (GSTM1, GSTT1, and GSTP1) and susceptibility to breast cancer [2].
• For GSTM1, the assignment was confirmed by Southern blot hybridization to a pair of 12.5/2.4-kb HindIII fragments [18].
• The GSTM1 null genotype occurred at a significantly lower frequency in the AMI patient group (48%) compared both to patients with no history of AMI (59%) and to the control group (57.2%) [40].
• Among patients treated with nitrosoureas (n = 108), those with GSTP1*A/*A and GSTM1 null genotype were 5.7 times (95% confidence interval, 0.9-37.4) more likely to experience an adverse event secondary to chemotherapy, compared with the others [41].
• While conventional PCR assays for detection of the GSTM1 deletion differentiated homozygously deficient from hetero- or homozygously active individuals, this long PCR assay differentiates homozygously active from hetero- or homozygously deficient individuals [42].

References