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  • POLYMORPHISMS  (7)
Keywords
  • 1
    Keywords: CANCER ; LUNG ; EMPHYSEMA ; FOLLOW-UP ; lung cancer ; LUNG-CANCER ; NETWORKS ; DEATH ; DISEASE ; DNA adducts ; EXPOSURE ; RISK ; GENES ; TIME ; DNA ; AIR-POLLUTION ; ASSOCIATION ; POLYMORPHISMS ; AGE ; REPAIR ; smoking ; leukemia ; bladder cancer ; BLADDER-CANCER ; cancer risk ; DAMAGE ; POLYCYCLIC AROMATIC-HYDROCARBONS ; DNA-DAMAGE ; RECRUITMENT ; ADDUCTS ; case-control studies ; EPIC ; nutrition ; QUESTIONNAIRE ; WHITE BLOOD-CELLS ; DNA-ADDUCTS ; case-control study ; DETERMINANTS ; monitoring ; GSTM1 ; LEVEL ; ADDUCT ; case control studies ; INTERVAL ; DNA damage ; DNA ADDUCT ; ABILITY ; GENDER ; OUTDOOR AIR-POLLUTION ; OZONE
    Abstract: Objectives were to investigate prospectively the ability of DNA adducts to predict cancer and to study the determinants of adducts, especially air pollutants. DNA adducts were measured in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC investigation. Cases included newly diagnosed lung cancer (n = 115), upper respiratory cancers (pharynx and larynx, n 82), bladder cancer (n = 124), leukemia (n = 166), and chronic obstructive pulmonary disease or emphysema deaths (n = 77) accrued after a median follow-up of 7 years among the EPIC former smokers and never-smokers. Three controls per case were matched for questionnaire analyses and two controls per case for laboratory analyses. Matching criteria were gender, age, smoking status, country of recruitment, and follow-up time. Individual exposure to air pollution was assessed using concentration data from monitoring stations in routine air quality monitoring networks. Leukocyte DNA adducts were analyzed blindly using (32)p postlabeling technique. Adducts were associated with the subsequent risk of lung cancer, with an odds ratio (OR) of 1.86 [95% confidence interval (95% CI), 0.88-3.931 when comparing detectable versus nondetectable adducts. The association with lung cancer was stronger in never-smokers (OR, 4.04; 95% CI, 1.06-15.42) and among the younger age groups. After exclusion of the cancers occurring in the first 36 months of follow-up, the OR was 4.16 (95% CI, 1.24-13.88). A positive association was found between DNA adducts and ozone (O-3) concentration. Our prospective study suggests that leukocyte DNA adducts may predict lung cancer risk of never-smokers. Besides, the association of DNA adduct levels with O-3 indicates a possible role for photochemical smog in determining DNA damage
    Type of Publication: Journal article published
    PubMed ID: 16140979
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  • 2
    Keywords: CANCER ; LUNG ; PATHWAY ; PATHWAYS ; PHASE-I ; lung cancer ; LUNG-CANCER ; COHORT ; RISK ; ENZYMES ; GENE ; GENES ; PATIENT ; RISK-FACTORS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; SUSCEPTIBILITY ; VARIANTS ; BREAST-CANCER ; DELETION ; NO ; STRESS ; AGE ; SNP ; smoking ; leukemia ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; bladder cancer ; BLADDER-CANCER ; cancer risk ; gene-environment interaction ; INVOLVEMENT ; case-control studies ; TOBACCO ; OXIDATIVE STRESS ; European Prospective Investigation into Cancer and Nutrition ; nutrition ; glutathione-S-transferase ; DNA-ADDUCTS ; SINGLE ; ONCOLOGY ; case control study ; case-control study ; ASSOCIATIONS ; PATTERN ; VARIANT ; ALLELE ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; interaction ; GSTM1 ; METHYLENETETRAHYDROFOLATE REDUCTASE ; MTHFR ; ALLELES ; case control studies ; ENVIRONMENTAL TOBACCO-SMOKE ; INTERVAL ; ENZYME ; methods ; PHASE ; single-nucleotide ; pooled analysis ; prospective ; CANDIDATE ; NEVER SMOKERS ; CANCERS ; CANCER-RISK ; Phase I ; SET ; case control ; METABOLIC PATHWAYS ; GENETIC-SUSCEPTIBILITY ; nonsmokers ; METHYLENE-TETRAHYDROFOLATE REDUCTASE ; metabolic genes ; NULL-GENOTYPE
    Abstract: Background: We chose a set of candidate single nucleotide polymorphisms (SNPs) to investigate gene-environment interactions in three types of cancer that have been related to air pollution (lung, bladder and myeloid leukemia). Patients and methods: The study has been conducted as a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (409 cancer cases and 757 matched controls). We included never and ex-smokers. SNPs were in genes involved in oxidative stress, phase I metabolizing genes, phase 11 metabolizing genes and methylenetetrahydrofolate reductase (MTHFR). Results: The most notable findings are: GSTM1 deletion and bladder cancer risk [odds ratio (OR) = 1.60; 95% confidence interval 1.00-2.56]; CYP1A1 and leukemia (2.22, 1.33-3.70; heterozygotes); CYP1B1 and leukemia (0.47, 0.27-0.84; homozygotes); MnSOD and leukemia (1.91, 1.08-3.38; homozygotes) and NQO1 and lung cancer (8.03, 1.73-37.3; homozygotes). Other statistically significant associations were found in subgroups defined by smoking habits (never or ex-smokers), environmental tobacco smoke or gender, with no obvious pattern. When gene variants were organized according to the three main pathways, the emerging picture was of a strong involvement of combined phase I enzymes in leukemia, with an OR of 5 (1.63-15.4) for those having three or more variant alleles. The association was considerably stronger for leukemias arising before the age of 55
    Type of Publication: Journal article published
    PubMed ID: 17496311
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  • 3
    Keywords: RISK ; POLYMORPHISMS ; smoking ; DNA-REPAIR GENES ; TRANSITIONAL-CELL CARCINOMA ; LOCI ; CHINESE POPULATION ; SEQUENCE VARIANTS ; CONFERS SUSCEPTIBILITY ; FLUID INTAKE
    Abstract: Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 x 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC
    Type of Publication: Journal article published
    PubMed ID: 21750109
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  • 4
    Keywords: EXPRESSION ; DISEASES ; RISK ; POLYMORPHISMS ; DNA-REPAIR GENES ; METAANALYSIS ; UROTHELIAL CELL-CARCINOMA ; imputation ; CONFERS SUSCEPTIBILITY ; SEQUENCE VARIANT
    Abstract: Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 x 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.
    Type of Publication: Journal article published
    PubMed ID: 24861552
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  • 5
    Keywords: CANCER ; LUNG ; MODEL ; PATHWAY ; PATHWAYS ; lung cancer ; LUNG-CANCER ; COHORT ; cohort studies ; cohort study ; DEATH ; DISEASE ; DISEASES ; DNA adducts ; RISK ; RISKS ; GENE ; GENES ; DNA ; RISK-FACTORS ; AIR-POLLUTION ; polymorphism ; POLYMORPHISMS ; BREAST-CANCER ; LESIONS ; DESIGN ; DNA-REPAIR ; REPAIR ; risk factors ; smoking ; bladder cancer ; BLADDER-CANCER ; cancer risk ; MUTATIONS ; ADDUCTS ; case-control studies ; OXYGEN ; DNA repair ; EXCISION-REPAIR ; reactive oxygen species ; case-control study ; VARIANT ; air pollution ; INCREASE ; SINGLE NUCLEOTIDE POLYMORPHISMS ; FUNCTIONAL-CHARACTERIZATION ; XPD POLYMORPHISMS ; case control studies ; INTERVAL ; RISK-FACTOR ; CANCER-RISK ; N-NITROSO COMPOUNDS ; BASAL-CELL CARCINOMA ; CHROMOSOME 19Q13.2-3 ; GENE XRCC3
    Abstract: Environmental carcinogens contained in air pollution, such as polycyclic aromatic hydrocarbons, aromatic amines or N-nitroso compounds, predominantly form DNA adducts but can also generate interstrand cross-links and reactive oxygen species. If unrepaired, such lesions increase the risk of somatic mutations and cancer. Our study investigated the relationships between 22 polymorphisms (and their haplotypes) in 16 DNA repair genes belonging to different repair pathways in 1094 controls and 567 cancer cases (bladder cancer, 131; lung cancer, 134; oral-pharyngeal cancer, 41; laryngeal cancer, 47; leukaemia, 179; death from emphysema and chronic obstructive pulmonary disease, 84). The design was a case-control study nested within a prospective investigation. Among the many comparisons, few polymorphisms were associated with the diseases at the univariate analysis: XRCC1-399 Gln/Gln variant homozygotes [odds ratios (OR) = 2.20, 95% confidence intervals (CI) = 1.16-4.17] and XRCC3-241 Met/Met homozygotes (OR = 0.51, 95% CI = 0.27-0.96) and leukaemia. The recessive model in the stepwise multivariate analysis revealed a possible protective effect of XRCC1-399Gln/Gln in lung cancer (OR = 0.22, 95% CI = 0.05-0.98), and confirmed an opposite effect (OR = 2.47, 95% CI = 1.02-6.02) in the leukaemia group. Our results also suggest that the XPD/ERCC1-GAT haplotype may modulate leukaemia (OR = 1.28, 95% CI = 1.02-1.61), bladder cancer (OR = 1.38, 95% CI = 1.06-1.79) and possibly other cancer risks. Further investigations of the combined effects of polymorphisms within these DNA repair genes, smoking and other risk factors may help to clarify the influence of genetic variation in the carcinogenic process
    Type of Publication: Journal article published
    PubMed ID: 16308313
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  • 6
    Keywords: CANCER ; CELLS ; CELL ; COMMON ; RISK ; GENE ; GENES ; DNA ; CARCINOGENESIS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; SUSCEPTIBILITY ; VARIANTS ; CHROMOSOMAL-ABERRATIONS ; DNA-REPAIR ; REPAIR ; smoking ; cancer risk ; DAMAGE ; RISK FACTOR ; TOBACCO ; DNA repair ; EXCISION-REPAIR ; TRANSITIONAL-CELL CARCINOMA ; SINGLE ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; XRCC1 POLYMORPHISMS ; LEVEL ; GENOTYPE ; USA ; cancer research ; RISK-FACTOR ; CANCER-RISK ; COMMON VARIANT ; NAT2 ; REPAIR GENES ; CONSORTIUM ; ERCC2 ; COMMON VARIANTS ; CONFIDENCE ; XPC POLYMORPHISMS
    Abstract: Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01-1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01-1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% Cl, 1.00-1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis. [Cancer Res 2009;69(17):6857-64]
    Type of Publication: Journal article published
    PubMed ID: 19706757
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  • 7
    Keywords: CANCER ; human ; LUNG ; MODEL ; lung cancer ; LUNG-CANCER ; COHORT ; cohort study ; DISEASE ; DISEASES ; EXPOSURE ; GENE ; GENES ; COMPLEX ; COMPLEXES ; DNA ; REDUCTION ; ASSOCIATION ; FREQUENCY ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; FREQUENCIES ; NUMBER ; REPAIR ; leukemia ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; BLADDER-CANCER ; REGION ; DNA repair ; DNA-REPAIR GENES ; VARIANT ; FUNCTIONAL-CHARACTERIZATION ; CATECHOL-O-METHYLTRANSFERASE ; METHYLENETETRAHYDROFOLATE REDUCTASE ; prospective ; LUNG-CANCER RISK ; VARIABLES ; metabolic gene polymorphisms ; METABOLISM GENES
    Abstract: It is becoming increasingly evident that single-locus effects cannot explain complex multifactorial human diseases like cancer. We applied the multi-factor dimensionality reduction (MDR) method to a large cohort study on gene-environment and gene-gene interactions. The study (case-control nested in the EPIC cohort) was established to investigate molecular changes and genetic susceptibility in relation to air pollution and environmental tobacco smoke (ETS) in non-smokers. We have analyzed 757 controls and 409 cases with bladder cancer (n = 124), lung cancer (n = 116) and myeloid leukemia (n = 169). Thirty-six gene variants (DNA repair and metabolic genes) and three environmental exposure variables (measures of air pollution and ETS at home and at work) were analyzed. Interactions were assessed by prediction error percentage and cross-validation consistency (CVC) frequency. For lung cancer, the best model was given by a significant gene-environment association between the base excision repair (BER) XRCC1-Arg399Gln polymorphism, the double-strand break repair (DSBR) BRCA2-Asn372His polymorphism and the exposure variable 'distance from heavy traffic road', an indirect and robust indicator of air pollution (mean prediction error of 26%, P 〈 0.001, mean CVC of 6.60, P = 0.02). For bladder cancer, we found a significant 4-loci association between the BER APE1-Asp148Glu polymorphism, the DSBR RAD52-3'-untranslated region (3'-UTR) polymorphism and the metabolic gene polymorphisms COMT-Val158Met and MTHFR-677C 〉 T (mean prediction error of 22%, P 〈 0.001, mean CVC consistency of 7.40, P 〈 0.037). For leukemia, a 3-loci model including RAD52-2259C 〉 T, MnSOD-Ala9Val and CYP1A1-Ile462Val had a minimum prediction error of 31% (P 〈 0.001) and a maximum CVC of 4.40 (P = 0.086). The MDR method seems promising, because it provides a limited number of statistically stable interactions; however, the biological interpretation remains to be understood
    Type of Publication: Journal article published
    PubMed ID: 16956909
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