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

Much is now known about the carcinogens in cigarette smoke, their conversion to forms that react with DNA, and the miscoding properties of the resulting DNA adducts that cause the many genetic changes known to exist in human lung cancer. The chronic exposure of pulmonary DNA to a multitude of metabolically activated carcinogens is consistent with our current understanding of cancer as a disease resulting from many changes in key genes regulating growth. This review illustrates how this solid foundation of knowledge can be used to find new ways to prevent lung cancer. Three prevention-related topics are discussed: human uptake of tobacco carcinogens as a way of assessing risk and investigating mechanisms; individual differences in the metabolic activation and detoxification of carcinogens, which may relate to cancer susceptibility; and chemoprevention of lung cancer in smokers and ex-smokers. These new approaches are necessary as adjuncts to education and cessation efforts, which despite some success have not eliminated tobacco smoking.
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PMID:Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. 1214 32

The 8-oxoguanine DNA glycosylase (OGG1) repairs DNA by removing 8-hydroxyguanine, a highly mutagenic oxidative DNA adduct. Recently, the gene for OGG1 was cloned and several polymorphisms have been reported. Because environmental carcinogens produce 8-hydroxyguanine residues that potentially cause oncogenic mutations by mismatching to this modified base, the capacity to repair these lesions can be involved in cancer susceptibility. This study investigated the association between OGG1 Ser326Cys polymorphism and risk of the lung adenocarcinoma for Japanese by a prevalent case-control study in Japan. The subjects comprised 138 cases and 241 non-cancer outpatients as controls. OGG1 gene polymorphism was genotyped by a PCR-CTPP (polymerase chain reaction with confronting two-pair primers) method. The distribution of OGG1 Ser326Cys genotype among controls (Ser/Ser, 28.3%; Ser/Cys, 49.2%; and Cys/Cys, 22.5%) was not different from that among cases (Ser/Ser, 29.0%; Ser/Cys, 51.4%; and Cys/Cys, 24.0%). The sex-age adjusted odds ratio (OR) was 1.06 with 95% confidence interval (CI) 0.64-1.76 for Ser/Cys genotype and 0.81 with 0.44-1.52 for Cys/Cys genotype. The ORs according to the interval between diagnosis and study enrollment were also examined because the polymorphism was a potential prognostic factor of lung cancer. The ORs of Ser/Cys and Cys/Cys genotypes in the cases less than 3 years after diagnosis were higher than overall ORs; 1.86 (95%CI, 0.91-3.77), and 1.46 (0.64-3.35), respectively. The OR for smoking was not statistically different among genotype, though the sample size was too small to detect even a moderate interaction. This study supported the first study by Sugimura et al (Cancer Epidemiol Biomarkers Prev, 1999; 8: 669-674), that the association of OGG1 Ser326Cys polymorphism was limited for the risk of lung adenocarcinoma.
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PMID:A limited association of OGG1 Ser326Cys polymorphism for adenocarcinoma of the lung. 1216 30

The role of human cytochrome P450 (CYP) in the metabolic activation of tobacco-related N-nitrosamines was examined by Salmonella mutation test using a series of genetically engineered Salmonella typhimurium YG7108 strains each co-expressing a form of CYP (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5) together with human NADPH-cytochrome P450 reductase. Seven tobacco-related N-nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, N-nitrosodiethylamine, N-nitrosopyrrolidine, N-nitrosopiperidine, N-nitrosonornicotine, N-nitrosoanabasine, and N-nitrosoanatabine were used. The CYP2A6 was found to be responsible for the mutagenic activation of essentially all tobacco-related N-nitrosamines examined. On the basis of the evidence, genetic polymorphism of the CYP2A6 gene appeared to be one of the factors determining cancer susceptibility caused by smoking. Previously, we found the whole deletion of the CYP2A6 gene (CYP2A6*4C) as a type of genetic polymorphism in Japanese. We hypothesized that individuals possessing the gene homozygous for CYP2A6*4C were incapable of activating tobacco-related N-nitrosamines and showed lower susceptibility to lung cancer induced by tobacco smoke. Thus, the relationship between the CYP2A6*4C and the susceptibility to the lung cancer was evaluated. The frequency of the CYP2A6*4C was significantly lower in the lung cancer patients than healthy volunteers, suggesting that the subjects carrying the CYP2A6*4C alleles are resistant to carcinogenesis caused by N-nitrosamines because of the poor metabolic activation capacity. Taking these results into account, CYP2A6 is an enzyme enhancing lung cancer risk.
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PMID:Role of human cytochrome P450 (CYP) in the metabolic activation of nitrosamine derivatives: application of genetically engineered Salmonella expressing human CYP. 1221 73

Green tea is widely consumed throughout the world and is known to possess various beneficial properties that may affect carcinogen metabolism, free radical scavenging, or formation of DNA adducts. Therefore, it is plausible that green tea extract may modify BPDE-induced DNA damage. In this report, we utilized the comet assay to (1) evaluate BPDE-induced DNA damage as a potential marker of cancer susceptibility and (2) assess the ability of green tea to modify BPDE-induced DNA damage. DNA damage in individual comet cells was quantified by (1) visually measuring the proportion of cells exhibiting migration versus those without and (2) the length of damaged DNA migration (comet tail). We detected a dose-response between BDPE concentration and mean comet tail length in EBV-immortalized lymphoblastiod (lymphoid) cell lines. As the concentration of BPDE increased from 0.5 to 3 microM, the length of the mean comet tail length increased proportionally in the 3590P (derived from a healthy subject) and 3640P (derived from a patient with head and neck cancer) cell lines. In separate experiments using lymphoid cells from 21 lung cancer cases and 12 healthy subjects, the mean comet tail length was significantly higher in the lung cancer cases (80.19 +/- 15.55) versus the healthy subjects (59.94 +/- 14.23) (P < 0.01). Similar findings were observed when analyzing the mean percentage of comet induced cells (84.57 +/- 8.85 and 69.04 +/- 12.50, respectively) (P < 0.01). When green tea extract was added in conjunction with BPDE, there was a notable reduction of the mean comet tail length (13.29 +/- 0.97) as compared to BPDE treatment alone (80.19 +/- 15.55) (P < 0.01) in lung cancer cases. There were no statistical differences between the baseline (no treatments) (12.74 +/- 0.63) and the green tea extract treatment (13.06 +/- 0.97) (P = 0.21). These data suggest the modification of lung cancer susceptibility by the green tea extract. Similar results were observed for the percentage of induced comet cells and the statistical trends were similar for the 12 healthy subjects. This preliminary study demonstrated that the detection of BPDE-induced DNA damage via the comet assay may be a useful biologic marker of lung cancer susceptibility. The differential effects in BPDE-induced DNA damage between lung cancer cases and healthy subjects suggests predisposed cancer susceptibility to lung cancer risk. This reports also demonstrated the chemopreventive effects of green tea extract on BPDE-induced DNA damage. These observations provide further support for the application of the comet assay in molecular epidemiologic studies.
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PMID:Modification of lung cancer susceptibility by green tea extract as measured by the comet assay. 1250 25

Adenocarcinoma is now the most common histological subtype of lung cancer;however, genetic factors that affect cancer susceptibility are largely unknown. In this study, we performed a systematic survey of the human genome with an average resolution of 10 cM to identify loci that could help us target novel risk genes for lung adenocarcinoma using linkage disequilibrium. Genotyping of DNA "pools" from 100 lung adenocarcinoma cases and 100 controls, respectively, for 322 microsatellite loci dispersed in the human genome led us to identify 5 loci at which allele distribution was significantly (P < 0.05) or marginally (0.05 </= P < 0.1) different between the cases and controls. One of the 5 loci, D19S246 at chromosome 19q13.3, showed significant differences both in the allele and genotype distributions in the subsequent analysis in which 239 lung adenocarcinoma cases and 63 controls were added to the 100 cases and 100 controls used for the initial screening (P = 0.037 and P = 0.026, respectively), whereas the remaining 4 loci did not. These results suggest that the chromosome 19q13.3 region encompassing D19S246 contains a gene(s) of which the genetic polymorphisms are associated with lung adenocarcinoma risk and are in linkage disequilibrium with the D19S246 locus.
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PMID:Identification of D19S246 as a novel lung adenocarcinoma susceptibility locus by genome survey with 10-cM resolution microsatellite markers. 1269 12

DNA repair plays a critical role in protecting the genome from insults of cancer-causing agents, such as those found in tobacco smoke. Therefore, reduced DNA repair capacity can increase the susceptibility to smoking-related cancers. Recently, several polymorphisms have been identified in the xeroderma pigmentosum group G (XPG) gene, and it is possible that these polymorphisms may affect the DNA repair capacity, thereby modulating cancer susceptibility. We investigated the relationship between the His1104Asp polymorphism in the XPG gene and the risk of lung cancer. The study population consisted of 310 lung cancer patients and 311 healthy controls who were frequency (1:1) matched based on age and sex. The Asp/Asp genotype was more frequent in the controls (28.9%) than in the cases (18.7%) and associated with a significantly decreased risk of lung cancer [adjusted odds ratio (OR) = 0.54, 95% confidence interval (CI) = 0.37-0.80] when the combined His/His and His/Asp genotype was used as the reference. The protective effect of the Asp/Asp genotype against lung cancer was statistically significant in the older subjects (adjusted OR = 0.51, 95% CI = 0.37-0.80), males (adjusted OR = 0.54, 95% CI = 0.35-0.83), and lighter smokers (adjusted OR = 0.48, 95% CI = 0.25-0.94) in a stratification analysis. When the lung cancers were analyzed by histologic type, the Asp/Asp genotype was associated with a significantly decreased risk of squamous cell carcinoma (adjusted OR = 0.55, 95% CI = 0.34-0.88) and small cell lung cancer (adjusted OR = 0.44, 95% CI = 0.20-0.97), but non-significant decreased risk of adenocarcinoma (adjusted OR = 0.64, 95% CI = 0.36-1.12). These results suggest that the XPG codon 1104 polymorphism contributes to genetic susceptibility to lung cancer.
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PMID:Relationship between XPG codon 1104 polymorphism and risk of primary lung cancer. 1286 23

Studies of familial aggregation of cancer provide indirect evidence for the role of genetic predisposition to cancer. In an ongoing case-control study, we evaluated whether first-degree relatives of lung cancer cases are at increased risk of lung and other cancers. Smoking-related cancers were defined as cancers of the lung, bladder, head and neck, kidney, and pancreas. The 806 probands included in this analysis were patients referred to The University of Texas M. D. Anderson Cancer Center (Houston, TX). We identified 663 controls, matched to the cases on age (+/-5 years), sex, ethnicity, and smoking history, who were recruited from a local multispecialty physician practice in the Houston metropolitan area. Self-reported cancer family history data were available for 6430 first-degree relatives of the cases and 4936 first-degree relatives of the controls. An excess of cancer in relatives was evaluated by comparing the observed cancer cases among relatives of the cases with relatives of the controls. We conducted further analysis after stratifying on age of lung cancer onset (age at study registration for controls) and smoking status (never, former, or current) of the probands. We also conducted Cox regression analysis and compared time to cancer diagnosis among the relatives of the cases and controls adjusted for age and smoking status of proband and family members. Siblings [relative risk (RR) = 1.85; P = 0.003] of cases had a significant excess of lung cancer and an excess of smoking-related cancers (RR = 1.29; P = 0.01). We observed evidence of familial aggregation (RR = 1.71; P < 0.001) of lung cancer among relatives of late-onset lung cancer cases. From the Cox regression, we observed a moderate risk for development of lung (RR = 1.25; P = 0.09) and other smoking-related cancers (RR = 1.23; P = 0.05). After adjustment for smoking behavior of probands and their relatives, the risks of lung cancer (RR = 1.33; P = 0.03) and smoking-related cancers (RR = 1.28; P = 0.02) were statistically significant. We further stratified on age at onset and observed no evidence (P = 0.81) of familial aggregation of lung cancer among young onset (<or=55 years of age) lung cancer cases. We also did not observe evidence of familial aggregation (P = 0.88) of smoking-related cancers in the same group. There was no evidence of increased risk (P = 0.77) of lung cancer among relatives of never-smokers. These findings support the need for additional study in the characterization and identification of genetic factors that influence and modulate cancer susceptibility in humans.
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PMID:Risk for smoking-related cancer among relatives of lung cancer patients. 1467 21

We applied an alternative approach to assess the controversial evidence for the role of GSTM1 and GSTT1 deficiencies (null genotypes) in cancer susceptibility. In this study setting, the prevalence of GSTM1 and GSTT1 null genotypes in the lung cancer patients (LCs, n = 167) were compared with those in the group of putatively cancer resistant individuals, i.e. elderly tumor-free donors (EDs, n = 324). Healthy middle-aged donors (HDs, n = 339) were used as another comparison group. Our results support the previous conclusions of a modest protective effect associated with presence of at least one functional copy of GSTM1 gene; the prevalence of GSTM1 deficiency in LCs (54%) did not differ from that observed in HDs (54%), but showed a significant increase when compared with EDs (45%) (OR = 1.46, 95% CI = 1.00-2.12). Furthermore, in agreement with mechanistic considerations, the GSTM1 null genotypes were more prevalent in squamous cell carcinoma patients (58%) and in lung cancer patients with seemingly low cumulative carcinogen exposure dose (non-smokers: 63%; patients aged below 50 years: 76%). Contrary to GSTM1, no significant effect in the lung cancer proneness was observed for the GSTT1 genotypes. The results of this study are thus in good agreement with the body of literature data, including several published meta-analyses. Consequently, the suggested study design involving additional "cancer resistant" group of non-affected subjects appears to provide highly demonstrative data and to be well suited for pilot investigations and for resolving controversial issues.
Lung Cancer 2004 Mar
PMID:A novel approach for assessment of cancer predisposing roles of GSTM1 and GSTT1 genes: use of putatively cancer resistant elderly tumor-free smokers as the referents. 1516 83

Functional genetic polymorphisms of DNA repair genes are good candidates for cancer susceptibility markers. We studied two genes coding for proteins removing small DNA adducts by direct repair (MGMT), or mispaired DNA bases by base excision repair (TDG). The non-silent polymorphisms of MGMT (84:Phe, 143:Val, 178:Arg) and TDG (199:Ser, 367:Met), and the functional MGMT enhancer polymorphism, did not show any statistically significant association with lung cancer risk in our case-control analysis, but due to the relatively small number of individuals, strong conclusions on cancer risk association or lack thereof cannot be made. Sequencing of the TDG cDNA has not revealed any novel polymorphism, but did find an alternatively spliced mRNA missing exon 2. Our search for polymorphisms within the promoter-enhancer region of MGMT revealed three novel sequence variants. The functional significance of the previously published MGMT enhancer polymorphism (1099C->T) was assessed. The less frequent sequence variant of the enhancer was associated with a modest (16-64%), but statistically significant, increase of MGMT promoter-enhancer activity in the studied cell lines. This work points to the importance of studying the expression-regulating elements of genes, as they may contain functional polymorphisms with the potential for modulating risk of various diseases, including cancer.
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PMID:Polymorphisms in TDG and MGMT genes - epidemiological and functional study in lung cancer patients from Poland. 1522 56

The mechanisms of p53-dependent apoptosis involve a set of genes that possess the ability to modulate oxidative stress. One of them PIG3, is induced by p53 through a microsatellite in its promoter region. This microsatellite was found to acquire its full structure and p53-functional dependence only in Hominoidea (apes and humans) and has been proposed to represent an evolutionary adaptation of tumor suppressor mechanisms. Microsatellite instability and genetic constitution, comprising the presence of the low repetition allele (10 TGYCC repeats), at this locus have been hypothesized to provide an increased risk for cancer development. Therefore, in the present analysis we examined this polymorphism in two common human cancers, lung and breast and compared it with corresponding control cases. Furthermore, for lung cancer we employed two different ethnic groups, Greek and British. Analysis of this locus in this types of tumors showed: (1) a very low frequency of microsatellite instability and loss of heterozygosity (1.4% and 4%, respectively) in the examined carcinomas, (2) the homozygous presence of the 10 repeats allele only in the control cases, and (3) a non-significant increase of the most frequent allele (15 repeats) in the cancer groups as compared to control ones. The last two observations were found in both Greek and British populations. Taken together, these data do not support the notion that this PIG3 polymorphism is associated with an increased risk for cancer susceptibility. Larger studies including other types of cancer should also be performed.
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PMID:Absence of association with cancer risk and low frequency of alterations at a p53 responsive PIG3 gene polymorphism in breast and lung carcinomas. 1549 42


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