Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The case-control study was conducted to examine the association between GSTM1 null and CYP2D6Ch (T(188)/T) genotypes and lung cancer risk among Chinese of Han nationality living in Guangdong. All 191 subjects were investigated with unitary questionnaire and their DNAs were isolated from peripheral lymphocytes by standard procedures with proteinase K digestion and phenol/chloroform extraction. GSTM1(-) was detected with polymerase chain reaction (PCR) in all 191 subjects, involving 59 lung cancer cases, 59 hospital controls and 73 healthy controls. The frequencies of GSTM1(-) were not significantly different between the cases and the two controls overall. However, among adenocarcinoma of lung, the frequency of GSTM1(-) (76.9%) appeared to be higher than that in controls (49.2%), and the odd radios were 3.42-3.45. The results suggested an elevated risk for adenocarcinoma of lung would be shown by GSTM1(-). Using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) to detect CYP2D6 T(188)/T genotype in 59 lung cancer patients and 59 hospital controls, it showed no significant difference between the two groups. However, non-smokers with non-T(188)/T (C(188)/C or C(188)/T) genotype showed 3.78-folds increased risk of lung cancer compared with those with T(188)/T genotype (P=0.036). The data did not suggest a substantial interaction effect between GSTM1 and CYP2D6 polymorphisms and the risk of lung cancer. Additionally, among Chinese (Han) of Guangdong, the frequency of CYP2D6 T(188) allele appeared to be 57.2%, and GSTM1(-) to be 51.8%.
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PMID:Polymorphisms of the GSTM1 and CYP2D6 genes associated with susceptibility to lung cancer in Chinese. 1052 84

The GSTM1 (glutathione S-transferase mu-1) null genotype is suspected of increasing an individual's susceptibility to tobacco smoke carcinogens because of impaired carcinogen detoxification. We were interested in whether there were differences in lung cancer susceptibility to smoking within the GSTM1 genotypes and the impact of antioxidant supplementation on this. For this purpose, we conducted a nested lung cancer case-control study and evaluated the role of GSTM1 within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. GSTM1 genotype status was determined for 319 cases and 333 controls using a PCR-based approach. GSTM1 was evaluated as an independent risk factor and as an effect modifier of smoking using logistic regression analyses. The GSTM1 null genotype itself was unrelated to risk of lung cancer, odds ratio (OR) = 1.09 and 95% confidence interval (CI), 0.79-1.50, but it may have modified the effect of smoking. There was a suggestion for a stronger association between years of smoking and lung cancer among the GSTM1 null genotype, but the differences between GSTM1 null and present genotypes were not statistically significant (P = 0.12). Furthermore, the smoking association was strongest among those with the GSTM1 null genotype not receiving alpha-tocopherol supplementation, whereas among those receiving alpha-tocopherol, there was no modification by GSTM1 on the association between smoking duration and lung cancer risk. Beta-carotene supplementation did not modify the relationship between GSTM1, smoking years, and lung cancer risk. In conclusion, GSTM1 is not associated with lung cancer risk in male smokers but may confer a higher susceptibility to cumulative tobacco exposure. This association may be attenuated by alpha-tocopherol but not by beta-carotene supplementation.
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PMID:Effect of vitamin intervention on the relationship between GSTM1, smoking, and lung cancer risk among male smokers. 1056 50

Preventive strategies require identification of cancer-susceptible individuals resulting from combinations of carcinogen exposure, cancer-predisposing genes, and lack of protective factors. To this aim, related to tobacco smoking and chewing (betel quid), we measured PAH-DNA adducts as exposure and susceptibility markers together with genetic polymorphism in drug-metabolizing enzymes related to CYP1A1, GSTM1, and GSTT1 genes in case-control studies. (+)-anti-Benzo(a)pyrene diol-epoxide (BPDE)-DNA adduct levels were quantitated in white blood cells (WBCs) and lung tissue DNA. CYP1A1 polymorphism and GSTM1 or GSTT1 gene deletion was analyzed in genomic DNA from lung parenchyma, WBCs, or oral biopsies (leukoplakia patients from India) and from oral exfoliated cells (healthy controls). Results from lung cancer patients and PAH-exposed coke oven workers correlated CYP1A1-GSTM1 genotype combinations with BPDE-DNA adduct levels. Smokers with homozygous CYP1A1 variant and GSTM1 null had the highest adduct levels and were, as shown in Japanese smokers, most susceptible to lung cancer. In oral premalignant leukoplakia cases associated with betel quid/tobacco chewing, the prevalence of the GSTM1 null and GSTT1 null genotypes was significantly higher, as compared to healthy controls. The combined GST null genotypes prevailed in 60% of the cases with none detected in controls. Based on this short review we conclude that (i) BPDE-DNA adduct levels resulting from "at risk" genotype combinations may serve as markers to identify most susceptible individuals; (ii) in Indian betel quid/tobacco chewers, the null genotypes of GSTM1 and GSTT1 greatly increased the risk for developing oral leukoplakia.
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PMID:Genetic cancer susceptibility and DNA adducts: studies in smokers, tobacco chewers, and coke oven workers. 1057 54

The modulation of benzo[a]pyrene diolepoxide (BPDE)-DNA adduct levels by polymorphisms in the CYP1A1, GSTM1 and GSTT1 genes was assessed in leukocytes of Caucasian males. Eighty-nine coke oven workers (35 smokers, 36 ex-smokers and 18 non-smokers) were recruited from job categories with different exposure levels to polycyclic aromatic hydrocarbons (PAH), together with 44 power plant workers (all smokers) not exposed to PAH. BPDE-DNA adducts were detected in 69 of 133 (52%) DNA samples with a 100-fold variation (range 0.2-44 adducts/10(8) nt) and a median of 1.6 adducts/10(8) nt. All samples with the GSTM1 active genotype (n = 59) and five out of 74 samples with GSTM1*0/*0 (7%) showed non-detectable adducts (<0.2 adducts/10(8) nt) and 69 of 74 subjects with GSTM1*0/*0 (93%) had detectable adducts (>0.2 adducts/10(8) nt). The difference in adduct level between the GSTM1*0/*0 and GSTM1 active genotypes was highly significant (P < 0.0001). No significant difference in adduct level between the GSTT1*0/*0 and GSTT1 active genotypes was seen. All heterozygotes (CYP1A1*1/*2) from subjects of GSTM1 active type did not have detectable adducts. Among the GSTM1-deficient individuals (n = 69), 42 with the CYP1A1*1/*1 genotype showed a lower adduct level (median 1.3, range 0.2-4.1 adducts/10(8) nt) compared with 26 individuals with heterozygous mutated CYP1A1*1/*2 genotypes (median 2.5, range 0.4-6.1 adducts/10(8) nt, P < 0.015). One individual with low PAH exposure and the rare combination CYP1A1*2A/*2A-GSTM1*0/*0 showed an extremely high level of 44 adducts/10(8) nt. Significant differences in detectable adduct levels were found between the CYP1A1*1/*1 and CYP1A1*1/*2 genotypes in the exposed group low + medium (P = 0.01) and for all adduct levels, detectable and non-detectable (set at a fixed value), in highly exposed individuals and in ex-smokers (P = 0.03), whereas no such differences were observed in the control group. Mutated CYP1A1*1/*2 increased the adduct level in non-smokers from the exposed group (1.4 versus 2.2 adducts/10(8) nt), but had no effect on the smokers from the exposed group (2.3 versus 2.8 adducts/10(8) nt). When all variables were dichotomized, statistical evaluation showed that CYP1A1 status (P = 0.015), PAH exposure (P = 0.003) and smoking (P = 0.006) had significant effects on adduct levels which increased in the order: CYP1A1*1/*1 < CYP1A1(*1/*2 or *2A/*2A); environmental exposure < occupational exposure; non-smokers < smokers, whereby adducts increased with cigarette dose and the duration of smoking. Higher levels of BPDE-DNA adducts in individuals with the combined CYP1A1(1/*2 or *2A/*2A)-GSTM1*0/*0 genotype suggest that these genotype combinations are at increased risk for contracting lung cancer when exposed to PAH.
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PMID:Modulation of benzo[a]pyrene diolepoxide-DNA adduct levels in human white blood cells by CYP1A1, GSTM1 and GSTT1 polymorphism. 1060 31

Glutathione S-transferase (GST) M1 polymorphism is a marker for susceptibility to smoking-related neoplasms, such as lung and bladder cancer. Recently, a genetic deletion of GSTT1, an isoenzyme of GST, has been reported to be associated with myelodysplastic syndromes (MDS). A 59-year-old man with a long-term smoking habit was treated successfully for non-small-cell lung cancer. Four years after the surgical removal of his lung cancer, he developed MDS and died. Using a polymerase chain reaction-based genotyping method, he was found to have a deletion of both the GSTM1 and GSTT1 genes. Screening for the deletion of the GSTM1 and GSTT1 genes may be useful for assessing individual genetic susceptibility to smoking-related lung cancer and MDS.
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PMID:A patient with genetic deletion of glutathione-S-transferase T1 and M1 who developed non-small-cell lung cancer and myelodysplastic syndromes. 1061 69

Interindividual differences in lung cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation of procarcinogens. GSTM1 status has been extensively studied in this context as a lung cancer risk factor, although published studies have produced conflicting results. To clarify the impact of GSTM1 status on lung cancer risk a meta-analysis of 23 case-control studies from the literature has been carried out using a random effects model. The principal outcome measure was the odds ratio for the risk of lung cancer. There was heterogeneity between the studies attributable to differences in the methods of assigning GSTM1 status. Pooling the studies that were based on phenotyping methods, the overall odds ratio of lung cancer risk associated with GSTM1 deficiency was 2.12 (95% confidence interval, 1.43-3.13). The risk of lung cancer risk associated with GSTM1 deficiency derived from the studies based on genotyping methods was, however, lower. The overall odds ratio was 1.13 (95% confidence interval, 1.04-1.25). These findings suggest that the estimates of lung cancer risk associated with GSTM1 deficiency in the early studies, based on phenotyping, were overinflated. Moreover, it is conceivable, given publication bias, that GSTM1 status has no effect on the risk of lung cancer per se. A major concern in case-control studies of polymorphisms and cancer risk is bias. A review of the 23 case-control studies indicates that greater attention should, therefore, be paid to the design of future studies.
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PMID:Glutathione S-transferase M1 status and lung cancer risk: a meta-analysis. 1074 27

The lung cancer mortality rate in Xuan Wei County, China is among the highest in the country and has been associated with exposure to indoor smoky coal emissions that contain high levels of polycyclic aromatic hydrocarbons. This risk may be modified by variation in metabolism genes, including GSTM1, which encodes an enzyme known to detoxify polycyclic aromatic hydrocarbons. To investigate the relationship between GST genotypes and lung cancer risk in Xuan Wei County, we analyzed GSTM1 and GSTT1 genotypes in a population-based case-control study. A total of 122 lung cancer patients and 122 controls, individually matched by age, sex, and home fuel type, were studied. Compared to subjects who used less than 130 tons of smoky coal during their lifetime, heavier users (> or =130 tons) had a 2.4-fold (95% confidence interval, 1.3-4.4) increased risk of lung cancer. The GSTM1-null genotype was associated with a 2.3-fold (95% confidence interval, 1.3-4.2) increased risk of lung cancer. Furthermore, there was some evidence that smoky coal use was more strongly associated with lung cancer risk among GSTM1-null versus GSTM1-positive individuals. In contrast, the GSTT1 genotype was not significantly associated with lung cancer risk. Our data suggest that the GSTM1-null genotype may enhance susceptibility to air pollution from indoor coal combustion emissions.
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PMID:Indoor coal combustion emissions, GSTM1 and GSTT1 genotypes, and lung cancer risk: a case-control study in Xuan Wei, China. 1086 96

Oxidative stress possibly contributes to the development of diabetic nephropathy. Therefore, the levels of endogenous antioxidants may be one of determinants of the susceptibility to diabetic nephropathy. Glutathione S-transferases (GSTs) can work as one of endogenous antioxidants to protect cells from oxidative stress. The M1 member of GST mu class (GSTM1) is polymorphic and only expressed in 55-60% of Caucasians because of the homozygous deletion of the gene (null genotype). Recent studies have provided evidence that the GSTM1 null genotype, i.e. lack of the GSTM1 activity, is associated with an increased susceptibility to lung cancer and colorectal cancer. The present study was conducted to determine whether the genetic polymorphism influences the development of diabetic nephropathy. We examined 105 patients with diabetic nephropathy and 69 patients without diabetic nephropathy in Japanese type 2 diabetic patients with proliferative diabetic retinopathy. GSTM1 genotyping was performed by polymerase chain reaction. The two patient groups were well matched with regard to age, body mass index and HbAlc. GSTM1 null genotype was observed in 48.6% of patients with nephropathy versus 55.1% of patients without nephropathy. The frequency of GSTM1 null genotype was not significantly higher in the patient group with nephropathy than in the patient group without nephropathy. This study is the first to investigate the association of GSTM1 gene polymorphism with the development of diabetic nephropathy. The present results suggest that GSTM1 null genotype does not contribute to the development of diabetic nephropathy in Japanese type 2 diabetic patients.
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PMID:No association of glutathione S-transferase M1 gene polymorphism with diabetic nephropathy in Japanese type 2 diabetic patients. 1090 Nov 85

Glutathione S-transferase (GST) polymorphism may contribute to the individual variability in detoxifying lung carcinogens. This effect might be particularly relevant at low-level exposure to environmental carcinogens, such as in nonsmokers exposed to environmental tobacco smoke (ETS). We conducted a case-control study among 122 nonsmoking lung cancer cases and 121 nonsmoking controls from eight countries. Information on environmental exposures was obtained through a personal interview. The presence of GSTM1 and GSTT1 genes was determined using multiplex PCR. GSTM1-positive samples were then analyzed for *1A and *1B polymorphism using an allele-specific amplification-PCR method. GSTM1*2 (null) individuals had an odds ratio (OR) of lung cancer of 1.5 [95% confidence interval (CI), 0.9-2.7]; the risk associated with this genotype was higher for cases with squamous and small cell carcinomas (OR, 2.3; 95% CI, 0.9-6.1) than for cases with adenocarcinomas. It was also elevated in individuals with long-term exposure to indoor wood combustion (OR, 3.1; 95% CI, 0.9-9.9), in subjects who mainly lived in a rural setting (OR, 3.6; 95% CI, 1.0-13), and in cases exposed to occupational carcinogens (OR, 10.7; 96% CI, 0.4-260) but not in subjects exposed to ETS. GSTT1*2 subjects did not show a risk of lung cancer. Our study suggests that the effect of GSTM1 polymorphism in nonsmokers is similar to that found in smokers. It does not seem to interact with ETS exposure, although we cannot exclude that it does in association with exposure to other specific environmental carcinogens.
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PMID:Lung cancer risk in nonsmokers and GSTM1 and GSTT1 genetic polymorphism. 1095

Cancer is known to be an extremely common disease, with the life-time risks reaching close to 0.5 for men and to 0.4 for women. Hence those individuals, who succeeded to achieve a reasonably old age without a history of malignancy, represent a distinct group of interest, which apparently can be defined as 'tumour-tolerant'. Focus on the genetic features of these subjects may significantly facilitate the research of cancer-predisposing polymorphisms: first, a fundamental understanding of molecular mechanisms conferring the phenomena of cancer resistance appears to be outstandingly important; second, it is promising to involve non-affected geriatric cohorts in the molecular epidemiological studies as a tumour-free control of especial value. Here we analysed the GSTM1 genotype frequencies in the individuals with seemingly different degrees of resistance or susceptibility to neoplasms, such as elderly tumour-free smokers and non-smokers (> or = 75-years-old), healthy middle-aged donors, and lung cancer patients. The proportion of GSTM1-deficient individuals gradually increased from elderly controls (70/157; 45%) to middle-aged ones (77/140; 55%) to lung cancer sufferers (34/58; 59%), showing the minimal estimates in elderly non-affected smokers (35/81; 43%) and the maximal ones in the affected non-smokers (7/7, 100%). These data have led to the two groups of conclusions. First, the broad protective role of GSTM1 has been confirmed in this report. In particular, GSTM1-deficiency appeared to reduce the chances of entering an elderly age without a history of malignancy (OR=0.66 (0.42-1.04); P=0.073). Second, the efficiency of 'tumour patients versus elderly donors' comparative analysis has been exemplified. Indeed, the long-debated fact of overrepresentation of GSTM1(-) genotypes among lung cancer sufferers was clearly demonstrated by comparison of the affected individuals to the geriatric controls (OR=1.76 (0.96-3.23); P=0.068), whereas the same patients failed to produce any convincing deviations towards the middle-aged donors (OR=1.16 (0.63-2.14); P=0.641).
Lung Cancer 2000 Sep
PMID:GSTM1 genotypes in elderly tumour-free smokers and non-smokers. 1099 21


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