UMLS:C0242379 - FACTA Search

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Query: UMLS:C0242379 (lung cancer)
71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Up to 90% of all cancers are possibly caused by environmental factors, such as tobacco smoke, diet and occupational exposures. The majority of chemical carcinogens require metabolic activation before they interact with cellular macromolecules and can cause cancer initiation. The xenobiotic-metabolising machinery contains two main types of enzymes: the phase-I cytochromes P-450 (CYP) mediating oxidative metabolism, and phase-II conjugating enzymes. Several phase-I and phase-II genes have recently been cloned and identified in humans. Many of them show polymorphism and have been suggested to contribute to individual cancer susceptibility as genetic modifiers of cancer risk. Altered phenotypes and genotypes in the CYP subfamilies CYP1A1, CYP2D6 and CYP2E1 have been associated with tobacco smoke-induced lung cancer and other cancers. Defective glutathione S-transferase (GST) and N-acetyltransferase (NAT) enzymes have been associated with an increased risk of developing lung and bladder cancer. There are also several studies in each category in which no associations have been found. The risk of developing lung cancer is dramatically (up to 40-fold) elevated in subpopulations having simultaneously high-risk genotypes in CYP1A1 and GSTM1. There are several difficulties in this area of research. First, many of the observed restriction-fragment length polymorphisms (RFLPs) are due to mutations in introns or other silent areas of DNA, raising the possibility that any associations found between RFLPs and cancer occur only by chance. Second, biologically plausible mechanisms linking genotypes and cancer are lacking in most of the observed cases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Diagnosis of polymorphisms in carcinogen-activating and inactivating enzymes and cancer susceptibility--a review. 760 65

Because of important roles of cytochromes P450 in the metabolic activation of many precarcinogens, extensive research in the past has focused on the relationship between the distribution of polymorphic variants of different isozymes of P450 and cancer susceptibility. In this respect three isozymes in particular have been studied, CYP1A1, CYP2D6, and CYP2E1. Both CYP1A1 and CYP2E1 participate in the metabolism of many suspected as well as established carcinogens, whereas essentially only one carcinogenic substrate has been identified for CYP2D6. Polymorphic sites for the three CYP genes have been identified both in the open reading frame as well as in introns and the regulatory 5' region. In the present contribution we summarize the molecular epidemiological research relating CYP polymorphism to cancer susceptibility and in some cases to toxicity. An interesting polymorphism has been described on the phenotypic level for the inducibility of CYP1A1, a polymorphism that in some studies has been related to a mutation in the 3' flanking region of the CYP1A1 gene. However, the genetic basis for this polymorphism might be inherited in the genes coding for proteins responsible for the induction of CYP1A1, ie, the Ah receptor or the ARNT protein. Data on lung cancer and CYP1A1 gene polymorphism indicate that carriers of genotypes associated with CYP1A1 inducibility are at higher risk for cancer, but that, at least for Caucasians, the recognized mutations probably identify only a fraction of the inducible individuals. The amount of DNA adducts correlates well in some studies to the individual activity registered for CYP1A1. CYP2D6 phenotype and genotype have mainly been related to the incidence of lung cancer, but results from 13 different studies now show an absence of any significant correlation between these parameters. In the case of CYP2E1, some studies indicate a relationship between lung cancer and the occurrence of a rare allele, although future research is needed in order to establish a significant relationship. It is concluded that, at the present stage, none of the polymorphic sites determined in the CYP genes can yet be used as markers for increased lung cancer risk. Future research in this field might be focused on the establishment of new polymorphic sites in the CYP genes, affecting inducibility or function, and on the molecular basis for the interesting differences in CYP1A1 inducibility.
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PMID:Genetic polymorphism of cytochromes P450 1A1, 2D6 and 2E1: regulation and toxicological significance. 762 Sep 40

Individual susceptibility to lung cancer due to occupational and environmental exposures to carcinogenic agents has been shown to be modulated by host-specific factors. The underlying principle of these factors is the differences that confer sensitivity or resistance to the disease. Since the majority of chemical carcinogens are not capable of causing hazardous effects per se, the metabolism of these compounds is a crucial part of the initial host response to the environmental exposure. Disturbances in the balance between activation and detoxification may thus explain the individual variations in responses to exposures to carcinogens. Many of the metabolic enzymes have recently been shown to express genetic polymorphisms in the population, and an association has been found between cigarette smoke-induced lung cancer and CYP1A1, CYP2D6, and GSTM1 genes. In addition, GSTM1 and NAT2 polymorphisms have been associated with susceptibility to bladder cancer. Since substantial ethnic differences exist in the distribution of altered and normal alleles, and findings in one ethnic group are not necessarily applicable to others, these biomarkers are still in the validation stage. However, as more information emerges on the specific features that lead to enhanced susceptibility they can undoubtedly be used to determine risks of environmental exposures to susceptible individuals and populations.
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PMID:Genetic factors in individual responses to environmental exposures. 762 Sep 41

Epidemiological studies have shown an increased incidence of lung cancer, bladder cancer, and esophageal cancer in chimney sweeps, probably due to their exposure to PAH in soot. The work environment for sweeps has, however, improved during the last decades. It was thus important to assess whether the present exposure still may cause genotoxic effects. A further objective was to assess whether genetic polymorphisms in metabolic enzyme activities could explain some of the variation in the parameters of genotoxicity. Venous blood samples were drawn from 71 chimney sweeps and 59 control subjects. Micronuclei were analyzed in activated peripheral B- and T-lymphocytes with preserved cytoplasm. Polymorphisms for CYP1A1 and GST1 in the sweeps were analyzed by a PCR technique. The sweeps did not have higher frequencies of micronuclei in B- or T-lymphocytes than the control subjects, when allowance was made for age and smoking in a multiple regression analysis. Further, there was no association between years of active work as a sweep and any of the two micronucleus parameters. None of the sweeps had the rare CYP1A1 genotype val/val and only one individual had the m2/m2 genotype. The presence of at least one GST1 allele (GST1+) was observed in 36 subjects (51.4%). Thirteen individuals (18.6%) were of the m1/m2 or m2/m2 genotype. And among those only seven had the combined GST1- and m1/m2 genotype. No difference was observed in B- or T-lymphocyte micronucleus frequencies between sweeps with the rare CYP1A1 genotypes m1/m2, m2/m2 or ile/val compared to individuals with the m1/m1 and ile/ile genotypes. Moreover, the GST1 deficient sweeps (GST1-) did not show any altered micronucleus frequency compared to the GST1 positive sweeps. A possible reason for the lack of genotoxic effect in sweeps is the improved hygienic conditions and change in fuels, which has decreased the exposure levels for PAH. Host polymorphisms for metabolizing enzymes did not influence the micronucleus frequencies. As the sweeps did not differ from the control subjects, with respect to micronucleus frequencies, no conclusion on the importance of host polymorphisms for genotoxic risk can be drawn.
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PMID:B- and T-lymphocyte micronuclei in chimney sweeps with respect to genetic polymorphism for CYP1A1 and GST1 (class Mu). 769 Aug 87

A case-control study on lung cancer in African-Americans has been conducted to assess whether a novel African-American-specific polymorphism in the CYP1A1 gene increases the susceptibility to tobacco-related lung cancer. The prevalence of the AA RFLP was 17.1% in the DNA extracted from archived tissue blocks from 76 incident cases of lung cancer, and was 16.3% in peripheral blood lymphocyte DNA of 123 healthy African-American volunteers recruited from a community in the eastern United States. The analysis by histological type showed an association between adenocarcinoma (AC) of the lung and the AA RFLP (odds ratio, 2.6; 95% confidence interval, 1.1-6.3). One homozygous variant subject was present among the AC cases. The risk of AC in subjects who both smoke and carry the AA RFLP was more than double, in comparison to subjects who only smoke (relative interaction magnitude under the additive model, 24%). The mean value of pack-year in AC with the polymorphism was 5.0 +/- 2.5 and in AC without the polymorphism was 37.2 +/- 6.5 (P < 0.05). Our data suggest that a selective association exists between the AA polymorphism and adenocarcinoma of the lung and that a lower dose of tobacco is sufficient to exert carcinogenic effects on the adenomatous tissue of subjects carrying the AA polymorphism.
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PMID:A specific African-American CYP1A1 polymorphism is associated with adenocarcinoma of the lung. 783 9

Polymorphism of CYP2D6 gene encoding for debrisoquine hydroxylase was determined genotypically for 94 controls and 77 lung cancer patients using a polymerase chain reaction-based application. Both of the point mutations that give rise to deficient alleles of the CYP2D6 gene are detectable by this method. Out of the 94 healthy controls, 3 individuals (3.2%) had poor metabolizer (PM) genotypes, whereas no PM genotypes were detected in the lung cancer patient group. We observed no difference in the allelic frequencies for either homozygous extensive metabolizers (EMs) or heterozygous EMs between the lung cancer patients and the healthy controls. However, the absence of the poor metabolizer genotype (0/77) in the lung cancer patients is compatible with the hypothesis that there is an increased risk of lung cancer for individuals who are extensive metabolizers of debrisoquine. Another member of the cytochrome P450 gene superfamily that has attracted interest for its potential role in human pulmonary carcinogenesis is the CYP1A1 gene. In CYP1A1 gene studies, a polymorphic site assessable to MspI gives rise to two different hybridizable fragments in a Southern blot analysis (alleles C1 and C2, respectively). The C2C2 genotype has previously been associated with an increased risk of lung cancer. So far 74 lung cancer patients, 30 patients with lung diseases other than cancer, and 118 healthy controls have been studied for CYP1A1 gene polymorphism. No association between the MspI restriction fragment length polymorphism in the CYP1A1 gene and lung cancer susceptibility has been found.
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PMID:Polymorphism in CYP1A1 and CYP2D6 genes: possible association with susceptibility to lung cancer. 790 63

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

At least two different polymorphisms in the human CYP1A1 gene have been associated with an increased risk for tobacco-related lung cancer; however, the functional significance of these polymorphisms has not been determined. We measured CYP1A1 genotypes, gene expression levels and enzymatic activity levels in mitogen-stimulated lymphocytes to determine whether genetic polymorphisms in CYP1A1 alter transcriptional and/or post-transcriptional regulation of the gene. Genotypes were determined at two sites previously associated with lung cancer: a point mutation in exon 7 near the catalytic region of the enzyme and an Msp1 RFLP in the 3' non-coding region of the gene. Variant genotypes at the Msp1 site had no effect on CYP1A1 gene induction, however, variant genotypes at the exon 7 site were significantly associated with increased CYP1A1 gene inducibility. We also observed a significant interaction between the exon 7 polymorphism and smoking on mRNA levels. There was a 3-fold elevation in CYP1A1 enzymatic activity in exon 7 variant genotypes. When Msp1 and exon 7 genotypes were combined, there was an increased CYP1A1 inducibility and enzymatic activity in subjects with the exon 7 polymorphism, and in subjects with both polymorphisms.
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PMID:Functional significance of different human CYP1A1 genotypes. 800 Dec 64

In a case-control study, we tested the hypothesis that a previously described African American-specific polymorphism in an intron 3' to the coding region of the CYP1A1 gene was associated with the occurrence of lung cancer. The study population included 72 African Americans with newly diagnosed, untreated lung cancer who presented to collaborating clinicians at the University of Texas M.D. Anderson Cancer Center and from county, community and Veterans Administration hospitals in the Houston metropolitan area. Controls were 97 African Americans, frequency-matched on gender and age, recruited from community centers, churches, cancer screening programs and from among hospital employees. The prevalence of the variant CYP1A1 genotype did not differ between the cases and controls. The odds ratio for individuals with one or more copies of the variant allele was 0.64 [95% confidence interval (CI) 0.3-1.4]. Overall, 20.7% of the population had one or more variant alleles; the prevalence in cases was 16.7% and in controls it was 23.7%. Two individuals with the homozygous variant genotype were controls while one individual with lung cancer was found to have the homozygous variant genotype. The lack of an association between genotype and lung cancer persisted after subgroup analysis for lifetime cigarette smoking history and tumor histology was performed. The sample size of this study is sufficient to detect odds ratios of three or greater; associations of this magnitude are similar to those reported in studies of a different polymorphism in the same region of the CYP1A1 gene in Japanese. Thus, it is unlikely that this polymorphism is associated with sizable risks for tobacco-induced lung cancer in this population subgroup.
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PMID:A race-specific genetic polymorphism in the CYP1A1 gene is not associated with lung cancer in African Americans. 802 Jan 43

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

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