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  • 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: CANCER ; CELL ; LUNG ; PATHWAY ; PATHWAYS ; lung cancer ; LUNG-CANCER ; EPIDEMIOLOGY ; RISK ; GENE ; GENES ; validation ; DNA ; BIOMARKERS ; cell cycle ; CELL-CYCLE ; SEQUENCE ; ASSOCIATION ; SUSCEPTIBILITY ; SUSCEPTIBILITY LOCUS ; VARIANTS ; HEALTH ; NUMBER ; REPAIR ; smoking ; p53 ; cancer risk ; FRANCE ; genotyping ; DNA repair ; TP53 ; ONCOLOGY ; VARIANT ; METAANALYSIS ; XRCC1 ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; biomarker ; analysis ; methods ; DNA repair genes ; pooled analysis ; USA ; cancer research ; CANCER-RISK ; OGG1 ; NOV ; GENOME-WIDE ASSOCIATION ; association study ; XRCC3 ; discussion ; POOLED-ANALYSIS ; CONSORTIUM ; genetic variants ; GENOME-WIDE ; APEX1
    Abstract: Background: The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. Methods: Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. Results: Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% Cl, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% Cl, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% Cl, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. Discussion: In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3081-9)
    Type of Publication: Journal article published
    PubMed ID: 18990748
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  • 4
    Keywords: CANCER ; BLOOD ; LUNG ; FOLLOW-UP ; lung cancer ; LUNG-CANCER ; DNA adducts ; EXPOSURE ; RISK ; SAMPLE ; SAMPLES ; DNA ; CARCINOGENESIS ; AIR-POLLUTION ; BIOMARKERS ; ASSOCIATION ; NO ; HUMANS ; DIFFERENCE ; REPAIR ; meta-analysis ; BLADDER ; bladder cancer ; BLADDER-CANCER ; cancer risk ; DAMAGE ; LYMPHOCYTES ; DNA-DAMAGE ; ADDUCTS ; CARCINOGENS ; case-control studies ; HEALTHY ; SMOKERS ; WHITE BLOOD-CELLS ; ALVEOLAR MACROPHAGES ; DNA-ADDUCTS ; ONCOLOGY ; case-control study ; INCREASE ; CARCINOGEN ; prospective studies ; LIFE ; METAANALYSIS ; LEVEL ; biomarker ; analysis ; DNA damage ; pooled analysis ; prospective ; prospective study ; ONSET ; COMPOUND ; CANCERS ; CANCER-RISK ; ENGLAND ; PREDICT ; POOLED-ANALYSIS ; HEAVY SMOKERS
    Abstract: Bulky DNA adducts are biomarkers of exposure to aromatic compounds and of the ability of the individual to metabolically activate carcinogens and to repair DNA damage. Their ability to predict cancer onset is uncertain. We have performed a pooled analysis of three prospective studies on cancer risk in which bulky DNA adducts have been measured in blood samples collected from healthy subjects (N = 1947; average follow-up 51-137 months). In addition, we have performed a meta-analysis by identifying all articles on the same subject published up to the end of 2006, including case-control studies. In the pooled analysis, a weakly statistically significant increase in the risk of lung cancer was apparent (14% per unit standard deviation change in adduct levels, 95% confidence interval 1-28%; using the weighted mean difference method, 0.15 SD, units higher adducts in cases than in controls). The association was evident only in current smokers and was absent in former smokers. Also the meta-analysis, which included both lung and bladder cancers, showed a statistically significant association in current smokers, whereas the results in never smokers were equivocal; in former smokers, no association was detected. The results of our pooled and meta-analyses suggest that bulky DNA adducts are associated with lung cancer arising in current smokers after a follow-up of several years
    Type of Publication: Journal article published
    PubMed ID: 18343884
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  • 5
    Keywords: DOWN-REGULATION ; CELL-CARCINOMA ; PULMONARY-FIBROSIS ; COMMON VARIANTS ; RECOMBINATION HOTSPOTS ; CHROMOSOME 8Q24 ; CONFERS SUSCEPTIBILITY ; UDP-GLUCURONOSYLTRANSFERASES ; TELOMERASE MUTATIONS ; SEQUENCE VARIANT
    Abstract: We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 x 10(-12)) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 x 10(-11)) on 19q12 maps to CCNE1 and rs11892031 (P = 1 x 10(-7)) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 x 10(-11)) and a tag SNP for NAT2 acetylation status (P = 4 x 10(-11)), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.
    Type of Publication: Journal article published
    PubMed ID: 20972438
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  • 6
    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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  • 7
    Abstract: Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P 〈 1 x 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 x 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 x 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P 〈/= 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
    Type of Publication: Journal article published
    PubMed ID: 26732427
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  • 8
    Keywords: CANCER ; CANCER CELLS ; CELLS ; BLOOD ; CELL ; human ; LUNG ; DIAGNOSIS ; FOLLOW-UP ; EXPOSURE ; PROTEIN ; PROTEINS ; PATIENT ; DNA ; CARCINOGENESIS ; ASSOCIATION ; HUMANS ; DESIGN ; PLASMA ; AGE ; MUTATION ; genetics ; smoking ; leukemia ; bladder cancer ; BLADDER-CANCER ; PCR ; CANCER-CELLS ; MUTATIONS ; RECRUITMENT ; CANCER-PATIENTS ; ADDUCTS ; case-control studies ; CANCER PATIENTS ; nutrition ; MULTICENTER ; lung neoplasms ; TP53 ; ADULT ; prospective studies ; PROTOONCOGENE ; HEALTHY-SUBJECTS ; INTERVAL ; CANCER DEVELOPMENT ; prospective ; prospective study ; healthy subjects ; female ; Male ; CANCERS ; LIQUID ; EXPOSURES ; Aged ; Middle Aged ; CANCER-DIAGNOSIS ; Genes,p53 ; Longitudinal Studies ; Proto-Oncogene Proteins ; Urinary Bladder Neoplasms
    Abstract: In cancer patients, plasma often contains mutant DNA released by cancer cells. We have assessed the significance of plasma DNA mutations for subsequent cancer development in healthy subjects in a large longitudinal prospective study. The European Prospective Investigation into Cancer and Nutrition study was analyzed with a nested case-control design. Cases were nonsmokers or ex-smokers for 〉10 years and newly diagnosed with lung, bladder, or upper aerodigestive tract cancers or leukemia accrued after a median follow-up of 6.3 years. Controls were matched 2:1 for follow-up, age, sex, area of recruitment, and smoking status. KRAS2 mutations were detected by mutant-enriched PCR and sequencing (n = 1,098). TP53 mutations were detected by denaturing high-performance liquid chromatography, temporal temperature gradient electrophoresis, and sequencing (n = 550). KRAS2 or TP53 mutations were detected in 13 of 1,098 (1.2%) and 20 of 550 (3.6%) subjects, respectively, 16 of whom developed cancer on average after 18.3 months of follow-up. Among 137 subjects who developed bladder cancer, 5 had KRAS2 mutations [odds ratio (OR), 4.25; 95% confidence interval (95% CI), 1.27-14.15] and 7 had TP53 mutations (OR, 1.81; 95% CI, 0.66-4.97). There was a nonsignificant trend for association between TP53 mutations and bulky adducts in lymphocyte DNA (OR, 2.78; 95% CI, 0.64-12.17). This is the first report of TP53 or KRAS2 mutations in the plasma of healthy subjects in a prospective study, suggesting that KRAS2 mutation is detectable ahead of bladder cancer diagnosis. TP53 mutation may be associated with environmental exposures. These observations have implications for monitoring early steps of carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 16818665
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  • 9
    Keywords: CANCER ; LUNG-CANCER ; COHORT ; DNA adducts ; EXPOSURE ; RISK ; DNA ; BIOMARKERS ; colon ; RATS ; CONTRAST ; BINDING ; ASSOCIATION ; COLORECTAL-CANCER ; BLADDER-CANCER ; cancer risk ; POLYCYCLIC AROMATIC-HYDROCARBONS ; COLON-CANCER ; MULTIVARIATE ; ADDUCTS ; CARCINOGENS ; DIET ; DIETARY ; ALCOHOL ; EPIC ; nutrition ; SMOKERS ; FOOD ; GUIDELINES ; VITAMIN-E ; DNA-ADDUCTS ; REGRESSION ; air pollution ; prospective studies ; N-NITROSAMINES ; LEVEL ; biomarker ; analysis ; prospective ; prospective study ; correlation ; BMI ; CANCER-RISK ; ENGLAND ; non-smokers ; AMINE ; gastrointestinal ; European Prospective Investigation into Cancer ; fibre intake ; haemoglobin adducts ; RESISTANT STARCH
    Abstract: In contrast to some extensively examined food mutagens, for example, aflatoxins, N-nitrosamines and heterocyclic amines, some other food contaminants, in particular polycyclic aromatic hydrocarbons (PAH) and other aromatic compounds, have received less attention. Therefore, exploring the relationships between dietary habits and the levels of biomarkers related to exposure to aromatic compounds is highly relevant. We have investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort the association between dietary items (food groups and nutrients) and aromatic DNA adducts and 4-aminobiphenyl-Hb adducts. Both types of adducts are biomarkers of carcinogen exposure and possibly of cancer risk, and were measured, respectively, in leucocytes and erythrocytes of 1086 (DNA adducts) and 190 (Hb adducts) non-smokers. An inverse. statistically significant, association has been found between DNA adduct levels and dietary fibre intake (P=0.02), vitamin E (P =0.04) and alcohol (P=0.03) but not with other nutrients or food groups. Also, an inverse association between fibre and fruit intake, and BMI and 4-aminobiphenyl-Hb adducts (P=0.03, 0.04, and 0.03 respectively) was observed. After multivariate regression analysis these inverse correlations remained statistically significant, except for the correlation adducts v. fruit intake. The present study suggests that fibre intake in the usual range can modify the level of DNA or Hb aromatic adducts, but Such role seems to be quantitatively modest. Fibres could reduce the formation of DNA adducts in different manners, by diluting potential food mutagens and carcinogens in the gastrointestinal tract, by speeding their transit through the colon and by binding carcinogenic substances
    Type of Publication: Journal article published
    PubMed ID: 18275627
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  • 10
    Keywords: CANCER ; CELL ; LUNG ; LUNG-CANCER ; RISK ; GENE ; PROTEIN ; ASSOCIATION ; SUSCEPTIBILITY LOCUS ; VARIANTS ; BREAST-CANCER ; genetics ; COLORECTAL-CANCER ; PROSTATE-CANCER ; MELANOMA ; VARIANT ; telomere length ; RISK-FACTOR ; BASAL-CELL CARCINOMA ; GENOME-WIDE ASSOCIATION ; SCAN ; COMMON VARIANTS
    Abstract: The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma(1), we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P 〈 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene
    Type of Publication: Journal article published
    PubMed ID: 19151717
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