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

Myeloperoxidase, which is released from neutrophils in response to various pulmonary insults including tobacco smoke, is suspected to play a carcinogenic role in the lung. A G-to-A substitution polymorphism in the promoter region of the MPO gene has been suggested in in vitro studies to decrease gene transcription. We tested the association of this polymorphism with lung cancer in a population-based case-control study of 323 cases and 437 controls of Caucasian, Japanese, or Native Hawaiian ancestry in Hawaii. We found a marked difference in the frequency of the variant A allele among Caucasians (26%), Japanese (17%), and Hawaiians (13%). Overall, the variant allele was somewhat less frequent in cases than controls (P = 0.13). Individuals with the A/A genotype were found to be at a 50% decreased risk compared to those with two G alleles (95% confidence interval, 0.2-1.3). Although not statistically significant, this inverse association was suggested in both sexes and two of the three ethnic groups studied. Heterozygotes were at no decreased risk. Further work needs to clarify the functional relevance of the A allele in vivo and to confirm the inverse association of the A/A genotype with lung cancer in large epidemiological studies.
 ...
PMID:Association of the myeloperoxidase -463G-->a polymorphism with lung cancer risk. 1069 79

The cytochrome P450 family of enzymes is responsible for many of the initial metabolic conversions of procarcinogenic compounds in tobacco smoke to reactive metabolites. However, other enzyme-based systems such as myeloperoxidase (MPO) may also be involved in this metabolic process. MPO is a phase I metabolic enzyme that has a polymorphic region upstream of the gene that appears to reduce transcriptional activity. The polymorphic G-->A nucleotide base shift negates the binding region for the general transcription factor SP1. Thus, individuals with the variant allele may be provided with a protective effect due to decreased metabolic conversion of carcinogenic compounds in tobacco smoke. This study has investigated the hypothesis that individuals with the variant allele may be at a reduced risk for lung cancer. Our results demonstrate that the protective effects of the MPO variant allele reduced overall lung cancer risk in Caucasians by 48% (OR = 0.52, 95% CI 0.30-0.90, P = 0.02). There was a 72% protective effect (OR = 0.28, 95% CI 0.12-0.61, P < 0.05) evident in men but not in women. Additionally, in younger individuals (<61 years) there was a statistically significant 72% reduction in risk (OR = 0.28, 95% CI 0. 11-0.69, P < 0.05) but not in older individuals. A protective effect was observed for current smokers (OR = 0.24, 95% CI 0.10-0.58, P < 0. 05) but not in former smokers and those who had never smoked. These data demonstrate that there is a reduction in lung cancer risk associated with a variant allele of MPO that is evident in men, younger individuals and current smokers.
 ...
PMID:Genetic variants of myeloperoxidase and lung cancer risk. 1083 5

Studies on the role of genetically polymorphic enzymes like cytochrome P450 1A1, arylamine N-acetyltransferase 2 or glutathione S-transferase M1 as cancer susceptibility factors date back more than 20 years, and some associations have been confirmed in several studies and meta-analyses. Overall, the extent of risk modulation due to these polymorphisms is only moderate but remains epidemiologically relevant. The role of some of these polymorphisms in human health may even be ambiguous: rapid acetylation, for example, protects from urinary bladder cancer but appears to increase the risk of laryngeal, lung and colon cancer. The first genetic polymorphisms in xenobiotics transporters such as P-gp (MDR1) and MRP2 have recently been identified. These polymorphisms may have great impact as cancer susceptibility factors as well as factors modulating the outcome of cancer treatment. Enzymes involved in generation or detoxification of reactive oxygen species also have to be considered; one of these enzymes, myeloperoxidase, constitutes a relatively strong lung cancer risk factor, as confirmed in 4 independent studies. Other genes, including those coding for DNA repair enzymes, signal transduction and cell growth regulation, may ultimately prove more important than the metabolic enzymes as cancer susceptibility factors. Study designs in molecular genetic epidemiology are evolving; large ongoing prospective trials increasingly allow confirmatory nested case control studies to be performed. However, carefully controlled, large case-control studies will remain the mainstay in molecular genetic epidemiology. Molecular genetic epidemiological evaluation of response to chemoprevention as well as response to the adverse events of cancer chemotherapy are likely to provide results that may be useful for individualized prevention and treatment in the near future. Since routine genotyping of all persons is now feasible, something like a genotype passport may soon become reality, and molecular and clinical epidemiological studies will have to provide the basis for understanding how to use genotype data for the benefit of the population.
 ...
PMID:Molecular genetics of cancer susceptibility. 1097 Dec 8

The effects of transfection of the metastasis suppressor gene nm23-H1 and cell-cycle related tumor-suppressor gene p16 on the activity of N-acetylglucosaminyltransferase V (GnT-V) and their relations to cancer metastatic potential were investigated. After transfection of nm23-H1 into 7721 human hepatocarcinoma cells and A549 human lung cancer cells, the activities of GnT-V were decreased by 28%-42% in the cells. In contrast, when p16 was transfected into these two cell lines, the decrease of GnT-V activity was only observed in A549 cells. This was probably to be due to the obvious expression of p16 gene in parental 7721 cells and the deletion of p16 in A549 cells. The decrease of GnT-V mRNA was only observed in nm23-H1-transfected cells, but not in p16-transfected A549 cells, suggesting that these two genes regulated GnT-V via different mechanisms. Horseradish peroxidase (HRP)-lectin staining showed that the 7721 cells transfected with nm23-H1 or the A549 cells transfected with p16 displayed a decreased intensity with HRP-leucoagglutinating phytohemagglutinin and increased intensity with HRP-concanavalin A, indicating the decline of beta1,6 N-acetylglucosamine branching structure on the asparagine-linked glycans of cell-surface and intracellular glycoproteins. The nm23-H1 transfected 7721 cells also displayed some changes in metastasis-related phenotypes, including the increase in cell adhesion to fibronectin (Fn), the decline in cell adhesion to laminin (Ln), and the decreased cell migration and invasion through matrigel. Transfection of antisense GnT-V cDNA into 7721 cells resulted in a decrease of GnT-V activity, an increase of cell adhesion to Fn or Ln, and a decrease in cell migration and invasion through matrigel. These phenotypes bore similarity to those of the 7721 cells transfected with nm23-H1. Our findings indicate that the down-regulation of GnT-V by nm23-H1 contributes to the alterations in metastasis-related phenotypes, and is an important molecular mechanism of metastasis suppression mediated by nm23-H1.
 ...
PMID:Down-regulation of N-acetylglucosaminyltransferase V by tumorigenesis- or metastasis-suppressor gene and its relation to metastatic potential of human hepatocarcinoma cells. 1097 75

In order to examine whether a polymorphism in the promoter region of the myeloperoxidase (MPO) gene is associated with lung cancer among male smokers, we conducted a case-control study nested within a Finnish clinical trial cohort. Although we found no evidence of an overall association between lung cancer risk and MPO genotype, the variant MPO genotype was associated with an increased risk of lung cancer among a subset of older men. These findings contrast with those from previous studies that report decreased lung cancer risk among MPO variant individuals.
 ...
PMID:Variation in the promoter region of the myeloperoxidase gene is not directly related to lung cancer risk among male smokers in Finland. 1117 31

This commentary was written to stimulate thoughts on, and consideration of, enzyme expression data in target organs when investigating possible associations between polymorphisms in carcinogen activation enzymes, lifestyle/dietary factors and cancer risk. The lung and breast are taken as examples. There is overwhelming evidence for a genotoxic mechanism in lung cancer development, and compelling evidence for the contribution of genotoxins to breast cancer aetiology. A consistent association has been shown where lung cancer risk is decreased by a G-->A polymorphism in the myeloperoxidase (MPO) gene, which is expressed in neutrophils recruited to the lung after chemical or immunological insults. In the breast, a consistent lack of association has been observed for women who are fast N:-acetyltransferase type 2 (NAT2) acetylators consuming cooked meat. This could be explained by the lack of detectable NAT2-associated sulfamethazine acetylation activity in cytosols prepared from mammary tissue, suggesting a minor contribution to carcinogen activation. The recent identification in mammary cytosols of detectable sulfotransferase isoforms (SULT1A1 and SULT1A3), which have high catalytic efficiency for activating N:-hydroxylated heterocyclic amines (HCAs, mutagens in cooked meat), offers a more important role for these enzymes in the metabolic activation of genotoxins in the breast. The possible contribution of MPO and lactoperoxidase enzymes to carcinogen activation in mammary tissue is also considered. Sulfotransferases and peroxidases have wide substrate specificity in terms of carcinogen activation (HCAs, aromatic amines and polycyclic aromatic hydrocarbons-all present in cooked meat and tobacco smoke) compared with NATs (HCAs and aromatic amines only). For gene-environment interactions, investigations into functional polymorphisms in SULT and peroxidase genes may, therefore, offer new evidence for the involvement of genotoxins in the initiation of carcinogenesis. Identification of the isoforms (if any) of carcinogen activation enzymes that are expressed in the organs of interest will help to determine which genes to investigate in these studies.
 ...
PMID:Single nucleotide polymorphisms, metabolic activation and environmental carcinogenesis: why molecular epidemiologists should think about enzyme expression. 1118 40

Activated human neutrophils secrete myeloperoxidase, which generates HOCl from H2O2 and Cl(-). We have found that various (2'-deoxy)nucleosides react with HOCl to form chlorinated (2'-deoxy)nucleosides, including novel 8-chloro(2'-deoxy)guanosine, 5-chloro(2'-deoxy)cytidine, and 8-chloro(2'-deoxy)adenosine formed in yields of 1.6, 1.6, and 0.2%, respectively, when 0.5 mM nucleoside reacted with 0.5 mM HOCl at pH 7.4. The relative chlorination, oxidation, and nitration activities of HOCl, myeloperoxidase, and activated human neutrophils in the presence and absence of nitrite were studied by analyzing 8-chloro-, 8-oxo-7,8-dihydro-, and 8-nitro-guanosine, respectively, using guanosine as a probe. 8-Chloroguanosine was always more easily formed than 8-oxo-7,8-dihydro- or 8-nitro-guanosine. Using electrospray ionization tandem mass spectrometry, we show that several chlorinated nucleosides including 8-chloro(2'-deoxy)guanosine are formed following exposure of isolated DNA or RNA to HOCl. Micromolar concentrations of tertiary amines such as nicotine and trimethylamine dramatically enhanced chlorination of free (2'-deoxy)nucleosides and nucleosides in RNA by HOCl. As the G-463A polymorphism of the MPO gene, which strongly reduces myeloperoxidase mRNA expression, is associated with a reduced risk of lung cancer, chlorination damage of DNA /RNA and nucleosides by myeloperoxidase and its enhancement by nicotine may be important in the pathophysiology of human diseases associated with tobacco habits.
 ...
PMID:Chlorination of guanosine and other nucleosides by hypochlorous acid and myeloperoxidase of activated human neutrophils. Catalysis by nicotine and trimethylamine. 1153 49

Idiopathic pulmonary fibrosis (IPF) is well known to be associated with lung cancer. Several atypical epithelial lesions are frequently observed in the fibrotic area in IPF patients, and they have been suspected to be related to lung carcinogenesis. Several studies have suggested that p53 protein accumulation and mutation occur in the early pathogenesis of squamous cell carcinoma of the lung, suggesting some abnormality of the p53 tumor-suppressor gene in interstitial lung diseases. To examine the cause of the high frequency of lung cancer in IPF, we examined the p53 changes in atypical epithelial lesions and carcinoma in patients with IPF by immunohistochemistry and mutational analysis. We examined 19 lung cancer patients with IPF who underwent surgical resection for lung cancer in our institute. Paraffin-embedded tissues were treated by microwave and stained with an anti-p53 antibody (RSP53) by the avidin-biotin-peroxidase complex method. Mutations in exons 5 through 8 of the p53 gene were also examined by polymerase chain reaction mediated single-strand conformation polymorphism (polymerase chain reaction-single-strand conformation polymorphism) analysis and DNA sequencing. p53 protein was immunohistochemically detected in 13 (62%) of 21 squamous cell carcinomas, 3 (60%) of 5 squamous metaplasia with atypia, 16 (54%) of 30 squamous metaplasia, and 1 (4%) of 26 other hyperplastic lesions. p53 mutation was detected in 12 (57%) of 21 squamous cell carcinomas, 2 (40%) of 5 squamous metaplasia with atypia, 7 (23%) of 30 squamous metaplasia, and 0 (0%) of 26 other hyperplastic lesions. In conclusion, there are frequent p53 gene alterations in squamous metaplasia, which is distributed in the peripheral zone of the fibrotic area in patients with IPF. The present findings might provide a clue to the molecular mechanisms underlying the high incidence of lung cancer, especially peripheral-type squamous cell carcinoma in IPF patients, and suggest that p53 gene alterations play an important role in the early stages of lung carcinogenesis in patients with IPF.
 ...
PMID:p53 gene alteration in atypical epithelial lesions and carcinoma in patients with idiopathic pulmonary fibrosis. 1167 37

Inactivation of the p16(INK4a) tumor suppressor gene and O(6)-methylguanine-DNA methyltransferase (MGMT) DNA repair gene by aberrant promoter methylation appears to be an important step in respiratory carcinogenesis after exposure to tobacco smoke and radon progeny. The determinants of aberrant promoter methylation are not well characterized. Polymorphic variants of genes of which the products are involved in pathways that modulate and repair DNA damage after carcinogen exposure may affect the occurrence of de novo promoter methylation. On the basis of their associations with risk of lung cancer, we hypothesized that functional polymorphic variants of the NADPH quinone oxidoreductase, glutathione S-transferases P1 and M1, myeloperoxidase, and XRCC1 genes are associated with p16 and/or MGMT promoter methylation in sputum from cancer-free subjects at high risk for developing lung cancer. This hypothesis was tested by conducting a cross-sectional study of 70 former uranium miners from the Uranium Epidemiological Study cohort who were at high risk for lung cancer. The polymorphic variant genotypes were characterized through PCR-RFLP on DNA isolated from peripheral lymphocytes, and the methylation status of the p16 and MGMT promoters was determined by methylation-specific PCR on DNA isolated from sputum. Subjects who had at least one GSTP1 polymorphic allele (A-to-G at bp 104) had an increased risk for MGMT methylation [odds ratio (OR), 4.8; 95% confidence interval (CI), 1.2-18.6] or for either p16 or MGMT methylation (OR, 4.4; 95% CI, 1.3-14.2). Lack of a wild-type NADPH quinone oxidoreductase allele (C at bp 609) was also associated with methylation of either p16 or MGMT (OR, 3.1; 95% CI, 1.0-9.2). These results provide the first link between germ-line functional deficits in pathways that protect the cell from tobacco- and radon-induced DNA damage, and the development of aberrant promoter methylation of the p16 and MGMT genes in the respiratory epithelium of individuals at high risk for lung cancer.
 ...
PMID:Glutathione S-transferase P1 and NADPH quinone oxidoreductase polymorphisms are associated with aberrant promoter methylation of P16(INK4a) and O(6)-methylguanine-DNA methyltransferase in sputum. 1195 78

Lung cancer is a major cause of cancer-related death in the developed countries and the overall survival rate has still an extremely poor. Cigarette smoking is an established risk factor for lung cancer although a possible role for genetic susceptibility in the development of lung cancer has been inferred from familial clustering of the disease and segregation analyzes. Everyone may have a unique combination of polymorphic traits that modify genetic susceptibility and response to drugs, chemicals and carcinogens. Developments in molecular biology have led to growing interest in investigation of biological markers, which may increase predisposition to lung carcinogenesis. Therefore, the high-risk genotype of an individual could be determined easily. As there are the great number of carcinogen-activating and -detoxifying enzymes, the variation in their expression and the complexity of exposures to tobacco carcinogens, the existence of multiple alleles at loci of those enzymes may result in differential susceptibilities of individuals. This review summarize data addressing the relationships of lung cancer to markers of genetic susceptibility genes, including metabolic polymorphisms other than well-investigated cytochrome P450s or glutathione S-transferases, DNA repair genes and the p53 tumor suppressor gene. Among genetic polymorphisms reviewed here, myeloperoxidase gene (a G to A mutation) and microsomal epoxide hydrolase exon 4 polymorphism (substitution of Arg for His) were significantly associated with lung cancer risk. As lung cancer is a multifactorial disease, an improved understanding of the interplay of environmental and genetic polymorphisms at multiple loci may help identify individuals who are at increased risk for lung cancer. Hopefully, in the future we will be able to screen for lung cancer susceptibility by using specific biomarkers.
Lung Cancer 2002 Sep
PMID:Genetic polymorphisms and lung cancer susceptibility: a review. 1223 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>