Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene deletion at the glutathione S-transferase mu locus (GSTM1) has previously been associated with increased risk for environmentally-induced cancers (e.g. smoking-related lung cancer). In the present study we examined the hypothesis that GSTM1 deletion is a risk factor for malignant brain tumors in adults. We compared the prevalence of the GSTM1 homozygous deletion polymorphism in 158 Caucasian adults with gliomas with 157 controls. Cases and controls were drawn from a large population-based case-control study of brain cancers in six San Francisco Bay area counties. Overall, the prevalence of the GSTM1 deletion was similar in cases (83/158; 53%) and controls (78/157; 50%). Among brain tumor cases, analysis of variance modeling indicated a significant interaction of GSTM1 genotype and gender associated with age at diagnosis (P = 0.02). This effect was due to the fact that women with GSTM1 deletion were younger on average at diagnosis than women who were GSTM1 positive (43.9 years versus 52.4 years, respectively). Age at diagnosis among men was similar for those who were GSTM1 deleted and GSTM1 positive (49.4 years and 47.2 years, respectively). The younger age at diagnosis of GSTM1 null female cases compared with GSTM1 positive cases was observed in astrocytoma as well as the higher grade tumors (e.g. glioblastoma multiforme). There was no association of GSTM1 deletion with age or gender in controls. These studies suggest that among female cases, GSTM1 deletion may be associated with earlier age at onset. Confirmation of these findings could provide important clues to gene-environment interactions in the etiology of malignant brain tumors.
Carcinogenesis 1997 Jul
PMID:Population-based study of glutathione S-transferase mu gene deletion in adult glioma cases and controls. 923 Feb 93

Basal cell carcinoma (BCC) is the commonest cancer in Caucasians. Its incidence is rising and many patients develop multiple primary tumours at separate sites. Factors determining time between first primary tumour presentation and the next new primary lesion are unclear. We used Cox's proportional hazards model to study, in 856 Caucasians, the influence of tumour site, individual characteristics and polymorphism in glutathione S-transferase (GSTM1, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) loci on time to next primary tumour presentation. More than one tumour at first presentation (P <0.0001, hazard ratio 2.72) and GSTT1 null (P = 0.028, hazard ratio 1.74) were associated with decreased time to next primary tumour presentation. Significant two-factor interactions, corrected for number of tumours at presentation, were identified between a truncal tumour at first presentation and each of male gender, GSTM1 null and CYP2D6 EM (P <0.003, hazard ratios 3.09-3.82). In each of these cases, all patients with the risk combination demonstrated further separate tumours within 5 years of first presentation. Thus, patients with a truncal tumour at first presentation, especially males and those presenting with more than one lesion have a significantly decreased time to presentation of further tumours and should receive more meticulous follow-up. Polymorphism in GSTM1 and CYP2D6 also influences the rate of new primary tumour accrual giving insights into the link between ultraviolet exposure and multiple tumour development.
Carcinogenesis 1997 Aug
PMID:Truncal site and detoxifying enzyme polymorphisms significantly reduce time to presentation of further primary cutaneous basal cell carcinoma. 927 22

Several polymorphic genes including those encoding for glutathione S-transferases (GST) have been reported to be involved in modifying lung cancer risk in smokers. The gene GSTM1 is frequently deleted in humans and a possible association between the null genotype and lung cancer risk is controversial. Another polymorphic gene of the same supergene family, GSTT1, is also involved in the detoxification of some environmental carcinogens. Both genes were genotyped in (a) a group of lung cancer patients (n = 160); (b) a group of healthy smokers (n = 120); (c) a group of blood donors from the general population (n = 192). All patients and controls were Northwestern Mediterranean Caucasians. The results show that the GSTM1 null genotype (GSTM1*0/GSTM1*0) was slightly over represented in the lung cancer patients (frequency of 58%; OR: 1.40, 95% CI: 0.74-2.61, referred to healthy smokers). The histological type most clearly modified was small cell carcinoma (frequency of 62.2%, OR: 1.91, CI: 0.78-4.69). The subdivision of the patients with one or two copies of the GSTM1 gene according to a GSTM1*A, GSTM1*B or GSTM1*A/B genotype (frequencies of 28.2%, 11.2%, 2.5% respectively) revealed no significant differences between the cases and both control groups. The frequency of the deleted GSTT1 genotype among the lung cancer patients (24%) was not significantly increased (OR: 1.08, CI: 0.57-2.05, referred to healthy smokers). The results showed that 14.4% of the patients presented homozygous deletion of both GSTT1 and GSTM1 (12.5% among healthy smokers) suggesting no potentiation between null genotypes for lung cancer risk.
Carcinogenesis 1997 Aug
PMID:Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms and lung cancer risk among Northwestern Mediterraneans. 927 26

Genotoxic effects linking cigarette smoking with lung cancer have not been consistently demonstrated, therefore claims for the cause-effect relationships are vigorously contested. Using matched populations of 22 lung cancer patients who have been cigarette smokers (LCP), 22 non-cancerous cigarette smokers (SC) and 13 non-smokers (NSC), we have applied the fluorescence in situ hybridization (FISH) tanden probe assay to elucidate the frequency of chromosome breakage among the participants. Two probes were used, a classical satellite probe which hybridizes to the large heterochromatin region of chromosome 1, and an alpha-satellite probe which targets a small region adjacent to the heterochromatin probe. The highest frequency of structural aberrations was observed in LCP (1.4 +/- 0.1) followed by SC (1.25 +/- 0.1) and NSC (0.4 +/- 0.1). Aberration frequencies were not significantly different between LCP and SC (p > 0.05), however, a statistically significant difference was detected between the smoker populations combined (LCP and SC) and the NSC (p < 0.001). The breakage frequencies showed a positive correlation with duration of smoking for LCP (r = 0.5; p < 0.01), but not for SC (P > 0.05). In addition, the aberration frequencies were influences by the inheritance of polymorphic glutathione S-transferase (GST) genes. LCPs missing one or the other GST (GSTM1 or GSTT1) genes were found to have significantly higher chromosome breaks compared to LCPs with both genes present (p < 0.05). Our data indicate that genetic predisposition and chromosome aberrations may be mechanistically related to the initiation of lung carcinogenesis; therefore, they may be useful biomarkers for lung cancer among cigarette smokers.
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PMID:Predisposing genes and increased chromosome aberrations in lung cancer cigarette smokers. 933 Jun 22

Xenobiotic metabolizing enzymes are known to play a role in the metabolic activation of environmental mutagens and carcinogens to exert their carcinogenic effects as well as detoxification by increasing their hydrophilicity. These enzymes include cytochrome P450s, glutathione S-transferases (GSTs), acetyltransferases (NATs) and sulfotransferases. Genetic polymorphisms in many of these enzymes, such as CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1, GSTP1 and GSTT1, have been shown to occur, which result in the altered expression of enzymatic activities. This suggests that the genetic polymorphisms may affect the individual susceptibility to environmental carcinogens and thus play a role in human carcinogenesis. Recently, the mutations that confer those polymorphisms of xenobiotic metabolizing enzymes have been identified and genotyping methods for the genetic polymorphisms have been developed. Specific phenotypes and genotypes for CYP1A1, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1 and GSTP1 have been associated with susceptibility to malignant diseases including lung, bladder and colon cancers, although the association was not confirmed in some studies. A number of factors such as degree of exposure to environmental carcinogens and the role of xenobiotic metabolizing enzymes in human carcinogenesis should carefully be evaluated in understanding genetic susceptibility.
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PMID:[Genetic polymorphisms in xenobiotic metabolizing enzymes as a determinant of susceptibility to environmental mutagens and carcinogens in humans]. 941 99

Susceptibility to lung cancer has been shown to be modulated by host specific factors. Inheritance of different polymorphic cytochrome P450s (CYPs) and the glutathione S-transferases (GSTs) which affect metabolism of environmental toxicants may play a key role in individual susceptibility. Although individual polymorphic genes have been reported to be associated with development of lung cancer, little is known about the combined effects of several genes in carcinogenesis. From our study of 54 lung cancer patients and 50 matched controls, we observed that a combination of several versions of 'unfavorable' metabolizing genes (CYP2D6, CYP2E1, GSTM1 and GSTT1) is strongly associated with lung cancer. The relative risk for the different combinations of these genotypes ranged between 1.3 and 14, with higher risk involving the activating genes. The duration and intensity of heavy smoking (expressed in pack-years) are the most important determinant for the development of lung cancer. For example, the estimated risk for development of lung cancer associated with smoking > 30 pack-years is represented by an odds ratio = 6.65; 95% CL = 2.3-19.9 irrespective of an individual's genotype, whereas for smoking between > 30 and < 50 pack years, odds ratio = 4.5; 95% CL = 1.37-15; and for smoking > 50 pack-years, odds ratio = 30; 95% CL = 5.7-114. On the other hand, smoking of less than 30 pack-years is associated with an increased risk in the presence of the polymorphic genes (odds ratio = 2.5; 95% CL = 0.32-54). The results of our study indicate that the inheritance of multiple 'unfavorable' genotypes, especially activating genes, is a crucial predisposing factor for the development of lung cancer from cigarette smoking. In addition, the genes may cause moderate smokers who would normally outlive the deleterious effects of smoking to develop lung cancer. The information can therefore be used to target individuals for prevention of health problems.
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PMID:Combined genetic polymorphism and risk for development of lung cancer. 943 75

Inactivation of tumor suppressor genes like p53 and p16 play a key role in tumor progression, with a high incidence of mutations existing for both genes in oral squamous cell carcinomas. Previous studies have demonstrated, (i) a correlation between the prevalence of p53 mutations and tobacco use [Brennan et al. (1995) New Engl. J. Med., 332, 712-717; Lazarus et al. (1996) Carcinogenesis, 17, 733-739], and (ii) a link between genotypes in specific xenobiotic metabolizing enzymes and oral cancer susceptibility [Park et al. (1997) Cancer Epid. Biomarkers Prev., 6, 791-797). In this paper, we present results of our examination of a series of 80 oral squamous cell carcinomas for p53 exons 5-9 and p16 exons 1-2 mutations, and the potential association of these mutations with specific genotyping patterns. p53 mutation prevalence in oral tumors was linked with increased patient tobacco use using several stratification criteria. There was a significantly higher prevalence of p53 mutations in OCSCCs from patients who smoked > 30 pack-years as compared to tumors from patients who smoked < or = 30 pack-years (OR = 2.8; CI = 1.1-7.2). No significant association was observed with patient alcohol consumption. There was a significant association between the prevalence of p53 mutations in oral tumors and CYP1A1 genotyping patterns in these oral cancer patients, with the highest p53 mutation prevalence observed in subjects with the CYP1A1 [val]/GSTM1 [+] genotype (OR = 6.0; CI = 1.2-29.7). A significant association was not observed between the prevalence of p16 mutations in oral tumors and tobacco use, or CYP1A1 [val] or GSTM1 (0/0) genotypes. These data suggest that the induction of mutations in specific tumor suppressor genes or oncogenes in oral tumors may be associated with specific carcinogen exposures, and that this association may be linked to specific polymorphic genotypes in xenobiotic-metabolizing enzyme genes.
Carcinogenesis 1998 Mar
PMID:p53, but not p16 mutations in oral squamous cell carcinomas are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use. 952 87

Relationships between smoking status and levels of bulky DNA adducts were investigated in bronchial tissue of lung patients in relation to their GSTM1 and CYP1A1 MspI genotypes. A total of 150 Hungarian patients undergoing pulmonary surgery were included in the study, 124 with lung malignancies and 26 with non-malignant lung conditions. There were significant relationships between smoking status and bulky DNA adduct levels, as determined by 32P-post-labelling analysis, in macroscopically normal bronchial tissues. There was a highly significant difference in the adduct levels of a combined group consisting of current smokers and short-term ex-smokers (< or = 1 year abstinence) compared with life-time non-smokers and long-term ex-smokers (> 1 year abstinence) (P = 0.0001). The apparent half-life was estimated to be 1.7 years for bulky DNA adducts in the bronchial tissue from ex-smokers. There were no statistically significant correlations between (i) daily cigarette dose and DNA adduct levels in current smokers, (ii) DNA adduct level and histological type of lung cancer, or (iii) GSTM1 and CYP1A1 MspI genotypes and DNA adduct levels after adjustment for either smoking status or malignancy. By multiple logistic regression analysis, smoking and GSTM1 null genotype were found to be risk factors for squamous cell carcinoma. However, bulky DNA adduct levels in bronchial tissue did not appear to be a statistically-significant risk factor for the major histological types of lung cancer.
Carcinogenesis 1998 May
PMID:Smoking-associated bulky DNA adducts in bronchial tissue related to CYP1A1 MspI and GSTM1 genotypes in lung patients. 963 72

Environmental related diseases due to occupational carcinogens and toxic substances are a serious problem particularly in developing countries. The glutathione S-transferase system is fundamental for the detoxification of numerous carcinogens and mutagens. The individual inherited susceptibility to chemical carcinogenesis due to glutathione S-transferase mu (GSTM1) and theta (GSTT1) varies significantly among distinct ethnic groups. In this study we determined the prevalence of the null genotype of the GSTM1 and GSTT1 genes among individuals from three distinct Brazilian racial groups using a multiplex-PCR methodology. The results showed that the highest prevalence of the null genotype for the GSTM1 occurred among Caucasians (55%, allele frequency = 0.74), followed by 33% among Brazilian Black subjects (allele frequency = 0.57), and 20% among Amazonian Indians (allele frequency = 0.45). For GSTT1 a homogenous distribution of the null genotype was found among Caucasian and African descendants (18.5 and 19% homozygotes, respectively, allele frequency = 0.43), with a lower prevalence among Amazonian Indians (11% of homozygotes, allele frequency = 0.34). Whether the deficiency of the GST system contributes to a predisposition to environmental related carcinogenesis in specific populations in Brazil remains to be determined.
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PMID:Prevalence of homozygosity for the deleted alleles of glutathione S-transferase mu (GSTM1) and theta (GSTT1) among distinct ethnic groups from Brazil: relevance to environmental carcinogenesis? 978 23

The human respiratory epithelium is in direct contact with chemical carcinogens and toxins in inhaled air. Therefore, the activities of xenobiotic-metabolising enzymes in this epithelium could modulate respiratory toxicity and carcinogenesis. We determined the expression of several xenobiotic-metabolising enzymes, including phase I and phase II enzymes, in human bronchial mucosa and peripheral lung tissues. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of phase I enzymes showed CYP1A1 and CYP2C (CYP2C8 and CYP2C18) mRNA expression in all of the 14 bronchial mucosa specimens. CYP2A6 and CYP2B6 mRNAs were found in 85% of the samples, whereas 50 and 90% of the tissues displayed CYP2E1 and CYP3A5 expression, respectively. However, CYP1A2, CYP2D6 and CYP3A4 mRNAs were not detected in all samples analysed. Normal human bronchial epithelial cells (NHBE cells) cultured in serum-free conditions showed reduced P450 expression in comparison with the bronchial mucosal samples. Similar to the bronchial mucosa, the peripheral lung tissues expressed CYP1A1, CYP2A6, CYP2B6, CYP2C (CYP2C8 and CYP2C18), CYP2E1 and CYP3A5 mRNAs, but did not show detectable levels of CYP2D6. Additional P450s, such as CYP1A2 and CYP3A4, were detected. The expression of CYP1A1, CYP1A2, CYP2B6, CYP2E1 and CYP3A4/5 in peripheral lung tissues was confirmed at the protein level, whereas CYP2A6 protein was undetectable. The use of specific primers for the detection of the phase II isoenzymes belonging to the glutathione S-transferase mu (GST mu) and N-acetyl transferase (NAT) families showed that GSTM1 was expressed in 40% of the bronchial mucosa and 25% of the peripheral lung tissues, whereas GSTM3 and NAT1 mRNAs were found in all bronchial and lung samples. Finally, NAT2 expression was detected in all peripheral lung tissues, but was not detected in the bronchus. In conclusion, these results describing the diversity of the xenobiotic-metabolising enzymes expressed in the bronchus and lung tissues indicate that the human respiratory system could significantly and specifically contribute to the activation and metabolism of several environmental procarcinogens.
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PMID:Characterisation of xenobiotic-metabolising enzyme expression in human bronchial mucosa and peripheral lung tissues. 979 7


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