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)

Genetically based differences in metabolism, related to MspI restriction site and Ile-Val polymorphisms of the cytochrome P450 (CYP) 1A1 gene and the null genotype of glutathione transferase class mu (GSTM1), have been reported to be associated with lung cancer susceptibility. The present study was set up to establish the frequencies of the polymorphic genotypes of CYP1A1 and GSTM1 in Sweden, to evaluate a possible increased incidence of the genotypes associated with higher lung cancer risks among Swedish lung cancer patients and to try to make a combined risk estimate for carriers of multiple risk alleles. In a healthy control group, all under 66 years of age, 53% (174/329) of the subjects were of the GSTM1(-) genotype, while in a hospital control group 49% (39/79) carried the GSTM1(-) genotype. In the investigated lung cancer patients this genotype was found in 56% (165/296) and among those patients diagnosed before 66 years of age the deficient genotype was found in 60% (78/131). The highest proportion of the GSTM1(-) genotype was found in patients diagnosed with adenocarcinoma (63%, 29/46) and small cell carcinoma (72%, 21/29) before 66 years of age and among female squamous cell carcinoma patients (79%, 15/19). The allelic variants in CYP1A1 were equally distributed in lung cancer patients and controls. The m1/m2 and m2/m2 genotypes of the MspI site and the Ile/Val genotype were, however, slightly over-represented in squamous cell carcinoma patients. Among patients with squamous cell carcinoma diagnosed before 66 years of age the m1/m2 genotype was found in 28% (10/36), whereas the same genotype was observed in 16% (52/329) of healthy control subjects. A combined risk of squamous cell carcinoma was indicated for patients, diagnosed before 66 years of age, carrying both GSTM1(-) and m2 alleles (OR = 3.0, 95% CI = 1.2-7.2).
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PMID:Genetic susceptibility to lung cancer with special emphasis on CYP1A1 and GSTM1: a study on host factors in relation to age at onset, gender and histological cancer types. 792 70

The combinations of the CYP1A1 inducibility and GSTM1 polymorphism have been investigated in relation to the histological type and peripheral or bronchial location of lung cancer in 54 surgically treated, current smoker lung cancer patients. The induced CYP1A1 was detected in 46 patients (85%) and the homozygous GSTM1 null genotype in 32 patients (59%). The role of CYP1A1 inducibility was found to be more important than that of GSTM1 polymorphism, because the non-inducible CYP1A1 was associated solely with bronchial tumours (P = 0.001), mainly squamous cell carcinomas. In patients with inducible CYP1A1, the expressing GSTM1 gene appeared to have a protective effect against contracting bronchial lung cancer, since 88% (14/16) of the lung tumours in this patient group were peripheral, whereas almost equal numbers of peripheral and bronchial tumours were observed in those patients lacking the gene (P = 0.037).
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PMID:Combined effect of CYP1A1 inducibility and GSTM1 polymorphism on histological type of lung cancer. 802 Jan 45

Recently, homozygous gene deletion of GSTM1, one of the Mu class glutathione S-transferase isozymes, was found to occur in approximately half of the population of various ethnic origins and has been implicated in tobacco-related carcinogenesis. In the present study we evaluated the risk of GSTM1 null genotype for lung cancer in relation to the extent of tobacco smoke exposure in 178 lung cancer patients (157 males, 21 females) and 201 healthy controls (140 males, 61 females), who were all Japanese and current smokers aged < or = 69 at the time of diagnosis. GSTM1 genotype was determined by polymerase chain reaction. We found GSTM1 gene to be lacking in 45.3% of the control population and demonstrated that the null genotype was aggregated a lot more in the squamous and small cell carcinoma groups (63-64%) than the control group but slightly more in the adenocarcinoma group (54.3%). Furthermore, when male patients and controls were analysed in relation to the degrees (< 800, 800-1200 and > or = 1200) of smoking index (sigma (cigarettes smoked per day) x (years of smoking)], the proportion of GSTM1 null genotype was found to increase progressively in the squamous and small cell carcinoma groups from 42-50% (odds ratio 0.8-1.3) in the patients with smoking index < 800 to 72-75% (odds ratio 3.1-3.7) in the patients with smoking index > or = 1200, while it was unrelated in the adenocarcinoma (50-55%, odds ratio 1.2-1.5) and in the control groups (42-48%). These results support the hypothesis that the GSTM1 null genotype is one of the genetic traits for smoking-related lung cancers, the risk of which, however, appears to be dependent on the extent of tobacco smoke exposure.
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PMID:Lung cancer risk of GSTM1 null genotype is dependent on the extent of tobacco smoke exposure. 831 38

The identification of genetic traits that predispose individuals to environmentally induced cancers is one of the challenges in the assessment of individual cancer risk. For this reason, individual variations in the expression of enzymes involved in biotransformation reactions have been extensively studied. One such polymorphic enzyme is GSTM1, which belongs to the class Mu of glutathione S-transferases (GSTs), and is only expressed in 55-60% of Caucasians. Previous data suggest that smokers lacking GSTM1 activity may be at greater risk of developing lung cancer. In this study, we used a polymerase chain reaction-based method to examine this issue in a Finnish study population. We found that 44% of a control group of 142 individuals lacked the GSTM1 gene, i.e. they had the GSTM1 null genotype; the rest were either homozygous or heterozygous for the expressed GSTM1 alleles. In a group of 36 patients with non-neoplastic pulmonary diseases, an identical distribution was observed. However, among 138 lung cancer patients the distribution of the GSTM1 genotypes deviated from that found in the healthy controls (53% nulled; odds ratio 1.5, 95% confidence interval 0.9-2.3). Furthermore, when the lung cancer patients were analysed by tumour type, a statistically significant increase in the GSTM1 null genotypes (62%; n = 71) was seen in the squamous cell carcinoma group, with an odds ratio of 2.1 (95% confidence interval 1.2-3.8). These data support the suggestion that GSTM1 null genotype may act as a risk modifier in lung cancer.
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PMID:The GSTM1 null genotype as a potential risk modifier for squamous cell carcinoma of the lung. 833 Mar 69

Mammalian cytosolic glutathione S-transferases (GSTs; EC 2.5.1.18) form a supergene family consisting of four distinct families, named alpha, mu, pi and theta. In humans one member of the mu class gene family (GSTM1) has been shown to be polymorphic and is only expressed in 55-60% of individuals. Previous studies have shown a possible link with the null phenotype and susceptibility to cancer, in particular to lung cancer. In this study we genotyped individuals with breast, bladder and colorectal cancer. A total of 490 individuals with cancer were studied, and consisted of 97 bladder, 197 breast and 196 colorectal cancers. No significant differences were observed in the frequency of nulled individuals in bladder or breast cancer patients when compared with a control population of 225 individuals. However, a significant excess of nulled individuals were seen in colorectal cancer: 56.1% compared with the control group value of 41.8%. This was shown to be highly significant depending on the site of the tumours and > 70% of individuals with a tumour in the proximal colon were GSTM1 nulled. This is an approximately 2-fold increase in colon cancer risk in these individuals.
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PMID:Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer. 840 4

Glutathione S-transferase class mu (GSTM1) is known to detoxify certain carcinogens or their activated metabolites. In a previous study using phenotyping methods, individuals genetically devoid of this enzyme activity were significantly overrepresented among lung cancer patients compared to controls, suggesting that this trait is a risk factor for lung cancer. Here, GST class mu status has been determined both pheno- and genotypically, i.e., (a) by ex vivo measurement of trans-stilbene oxide conjugation in lymphocytes, (b) by GSTM1 quantification in blood using an immunoassay, and (c) by the application of polymerase chain reaction to genomic DNA with characterization of an inactivating mutation responsible for the null allele and a G/C single base allelic variance corresponding to the polymorphism of GSTM1 isoenzymes mu and psi, respectively. One hundred seventeen lung cancer patients and 155 control patients were studied. The two groups were of German origin and were similar with respect to age, sex, smoking history, and catchment area. In about 97% of cases, the three methods of assigning activity type of GSTM1 gave corresponding results. By genotype, 55 of 117 lung cancer patients (47.0%) and 73 of 155 control patients (47.1%) were GSTM1 active. The control group was confirmed by analysis of GSTM1 genotype in 200 further, independently studied reference patients; 101 of them were GSTM1 active (50.5%). Thus, the hypothesis of heritable GSTM1 deficiency as a host factor predisposing to lung cancer proved inappropriate. Detailed analysis of subgroups with respect to smoking habits, age, and sex failed to reveal an impact of GST class mu genotype on lung cancer risk. Among the total of 272 patients studied, 36 individuals carried at least one psi allele; however, no unexpected frequency distribution was observed.
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PMID:Genotype and phenotype of glutathione S-transferase class mu isoenzymes mu and psi in lung cancer patients and controls. 843 46

We reported an association of smoking-induced lung cancer susceptibility with the human cytochrome P450 1A1 (CYP1A1) polymorphisms in our previous studies. 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. The frequency of p53 mutations among heavy smokers was higher than in patients who had never smoked [P < 0.01; odds ratio (OR), 3.74; 95% confidence interval (CI), 1.46-9.56]. By single-strand conformational polymorphism, aberrant migration bands of p53 gene fragments were detected in 56 cases (38%). Smokers with susceptible rare homozygous alleles of either the MspI or Ile-Val polymorphism of the CYP1A1 gene have a 4.5-fold (P < 0.005; OR, 4.48; 95% CI, 1.64-12.26) or 5.5-fold (P < 0.01; OR, 5.52; 95% CI, 1.55-19.64) higher risk of having a mutation of the p53 gene than those with nonsusceptible predominant homozygous alleles of the gene. Non-small cell lung cancer patients with a susceptible CYP1A1 genotype were at remarkably high risk of having a mutation of the p53 gene when the genotype was combined with a deficient genotype, GSTM1(-). However, there was no difference between the types of p53 mutation and genotypes of the drug-metabolizing enzymes. These results showed that CYP1A1 germ line polymorphisms, which were associated with the genetic predisposition for lung cancer, were related to cigarette smoking-associated p53 mutations.
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PMID:Association of CYP1A1 germ line polymorphisms with mutations of the p53 gene in lung cancer. 854 78

In the case of lung cancer induced by chemical carcinogens, cellular processes of metabolic activation and deactivation of these substances play a particular role. The involvement of glutathione--S-transferase in the process of deactivation of active metabolites draws special attention. Cellular activity of these enzymes is a significant factor which can define individual susceptibility to carcinogenic effect of occupational and environmental carcinogens. Glutathione--S-transferase catalyses the reaction of binding glutathione with a great number of pharmacologically active substances, including also those with genotoxic properties. These reactions protect cells against toxic and genotoxic effect of exo- and endogenous substances. They prevent among others, from producing adducts by genotoxic substances with macromolecules. Some of glutathione--S-transferases (the so-called ligands) act as proteins which bind and transport organic ligands in cells (bilirubin, steroid metabolites, bile acids). To date studies have not confirmed uni-vocally that low activity of glutathione--S-transferases be one of the reasons for an increased incidence of lung cancer. Observations of persons with phenotype of a low activity of glutathione--S-transferase (GSTM1-0) have indicated that the incidence of lung cancer is significantly higher among them than in persons with phenotype of normal activity of this enzyme. These observations, however, have not been confirmed by an analysis of relationship between the incidence of lung cancer and the genotype of low and normal activity of glutathione--S-transferase.
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PMID:[Glutathione S-transferase as a metabolic biomarker for predisposition to lung neoplasms induced by chemical carcinogens]. 855 56

CYP1A1 is responsible for the metabolic activation of benzo(a)pyrene in cigarette smoke, and high susceptibility to smoking-related lung cancer has been associated with the MspI polymorphism of the CYP1A1 gene. Individuals with a susceptible CYP1A1 genotype have been found to be at remarkably high risk when the genotype is combined with a deficient Mu-class glutathione S-transferase (GSTM1) genotype. In this study, we investigated the relationship between germ line polymorphisms of these genes and clinical characteristics or survival rates in 232 patients with non-small cell lung cancer (NSCLC). Statistical analysis revealed a significant association (P < 0.05) of the MspI polymorphism of the CYP1A1 gene with histological type, performance status (general conditions of patients), and the extent of the primary tumor (T-factor). On the other hand, the GSTM1 polymorphism was significantly associated with performance status, the extent of regional lymph node metastasis (N-factor), and the extent of distant metastasis (M-factor). NSCLC patients with at least one susceptible allele of the MspI polymorphism of the CYP1A1 gene [heterozygous genotype B or a rare homozygous genotype C; n = 131; median survival time (MST) = 24.2 months] were associated with a shortened survival compared with those with nonsusceptible homozygous alleles (genotype A; n = 101; MST = 65.2 months; P = 0.005 by log-rank test). Smokers with susceptible genotypes (n = 104; MST = 18.2 months) were markedly associated with a shortened survival compared with those with genotype A (n = 76; MST = 69.2 months; P = 0.024); such an association was not found among nonsmokers by genotypes. Genotype-dependent survival was also observed in patients at an advanced stage of disease (P = 0.010), but not in those at an early stage of disease (P = 0.382). Patients with the susceptible CYP1A1 genotype had remarkably shortened survivals when the genotype was combined with a deficient genotype GSTM1(-) (P = 0.017; degree of freedom = 3). Multivariate analysis by the Cox proportional hazards model also revealed that the CYP1A1 polymorphism was an independent prognostic factor in patients at a nonresectable advanced stage of NSCLC (P = 0.005; hazard ratio = 1.98; 95% confidence interval, 1.24-3.17).
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PMID:Prognostic significance of germ line polymorphisms of the CYP1A1 and glutathione S-transferase genes in patients with non-small cell lung cancer. 870 15

Most of chemical carcinogens require metabolic activation before they interact with cellular macromolecules and can cause cancer initiation. Many of cytochrome P-450 (CYP) mediating oxidative enzymes and conjugation enzymes, cloned and characterized in humans, show genetic and phenotypic polymorphisms and have been suggested to contribute to individual cancer susceptibility as genetic modifiers of cancer risk. Altered phenotypes and genotypes in CYP1A1, CYP2D6 and CYP2E1 and in defective glutathione S-transferase (GST) and N-acetyltransferase enzymes have been associated with an increased risk of developing lung and other cancers. The risk to lung cancer is dramatically increased in the population carried simultaneously high-risk genotypes in CYP1A1 and GSTM1. There are, however, several studies in each category in which no association have been found.
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PMID:[Genetic and phenotypic polymorphisms in carcinogen-metabolizing enzymes and cancer susceptibility]. 881 Aug 6


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