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  • ASSOCIATION  (13)
  • BREAST  (12)
  • COHORT  (7)
  • 11
    Keywords: PEPTIDE ; RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; tumor ; human ; RISK ; GENE ; SAMPLES ; TUMORS ; PATIENT ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; PROGRESSION ; AGE ; MUTATION ; TUMOR PROGRESSION ; SIGNALING PATHWAY ; MUTATIONS ; BLOOD-PRESSURE ; EPITHELIAL- CELLS ; FACTOR BETA-1 GENE ; GROWTH-FACTOR-BETA ; GROWTH-FACTOR-BETA-1 GENE ; HeLa cells ; MYOCARDIAL-INFARCTION ; T29-〉C POLYMORPHISM
    Abstract: There is evidence that transforming growth factor (TGF)beta acts as a suppressor of tumor initiation but also as a promoter of tumor progression when the antiproliferative effect of the TGFbeta signaling pathway has been overridden by other oncogenic mutations. Several somatic mutations that disrupt the TGFbeta-SMAD signaling pathway have been reported in human breast tumors. We have examined the association between single nucleotide polymorphisms (SNPs) in the TGFbeta1 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3987 patients and 3867 controls, median age similar to50 years, and range 22-92 years. The promoter SNP, C-509T, and the T +29C signal-peptide SNP (encoding Leu10Pro) are in strong linkage disequilibrium. They are both significantly associated with increased incidence of invasive breast cancer in a recessive manner [odds ratios: (TT versus C-carrier), 1.25; 95% confidence intervals 1.06-1.48; P = 0.009 and (ProPro versus Leu-carrier), 1.21; 95% confidence intervals 1.05-1.37; P = 0.01]. The G-800A SNP was not significantly associated with incidence of breast cancer. The C-509T SNP is not contained within a known consensus sequence for a promoter regulatory element and therefore unlikely to affect TGFbeta1 expression, whereas the Leu10Pro signal peptide substitution potentially affects TGFbeta1 secretion. Transfections of HeLa cells with constructs encoding either the Pro or Leu forms of TGFbeta1 and driven by the cytomegalovirus promoter indicate that the signal peptide with Pro at residue 10 causes a 2.8-fold increase in secretion compared with the Leu form. These data indicate that the allele encoding Pro10 is associated with increased rates of TGFbeta1 secretion and with increased incidence of invasive breast cancer for the population samples described. It is estimated that 3% of all breast cancer cases may be attributable to Pro10 homozygosity
    Type of Publication: Journal article published
    PubMed ID: 12750287
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  • 12
    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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  • 13
    Keywords: CANCER ; COHORT ; RISK ; GENE ; ASSOCIATION ; FREQUENCY ; LINKAGE ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; PATTERNS ; HEALTH ; WOMEN ; SNP ; PROSPECTIVE COHORT ; prostate cancer ; PROSTATE-CANCER ; cancer risk ; HUMAN GENOME ; REGION ; LINKAGE DISEQUILIBRIUM ; nutrition ; POSTMENOPAUSAL WOMEN ; ONCOLOGY ; ASSOCIATIONS ; RE ; INCREASE ; SNPs ; ESTROGEN ; LEVEL ; ENZYME ; analysis ; HAPLOTYPE ; HAPLOTYPES ; LOCUS ; single-nucleotide ; single-nucleotide polymorphism ; HORMONES ; prospective ; cancer research ; CANCER-RISK ; MULTIETHNIC COHORT ; BASE-LINE CHARACTERISTICS ; PREDICT ; NONCARRIERS ; AROMATASE
    Abstract: The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. In this study, we used a systematic two-step approach that included gene resequencing and a haplotype-based analysis to comprehensively survey common genetic variation across the CYP19A1 locus in relation to circulating postmenopausal steroid hormone levels and breast cancer risk. This study was conducted among 5,356 invasive breast cancer cases and 7,129 controls comprised primarily of White women of European descent drawn from five large prospective cohorts within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A high-density single-nucleotide polymorphism (SNP) map of 103 common SNPs (〉= 5% frequency) was used to identify the linkage disequilibrium and haplotype patterns across the CYP19A1 locus, and 19 haplotype-tagging SNPs were selected to provide high predictability of the common haplotype patterns. We found haplotype-tagging SNPs and common haplotypes spanning the coding and proximal 5' region of CYP-19A1 to be significantly associated with a 10% to 20% increase in endogenous estrogen levels in postmenopausal women [effect per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 4.4 X 10(-15)]. No significant associations were observed, however, with these SNPs or common haplotypes and breast cancer risk. Thus, although genetic variation in CM19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer
    Type of Publication: Journal article published
    PubMed ID: 17325027
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  • 14
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; HISTORY ; RISK ; SAMPLE ; TUMOR-NECROSIS-FACTOR ; FAMILY ; BIOMARKERS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; HEALTH ; AGE ; WOMEN ; SNP ; cancer risk ; GENOTYPES ; HETEROGENEITY ; FAMILIES ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; ESTROGEN ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; ALLELES ; biomarker ; GENOTYPE ; FAMILY-HISTORY ; USA ; CANCER-RISK ; Sample Size ; CONSORTIUM ; ERCC4 ; RECEPTOR STATUS ; PROGESTERONE-RECEPTOR GENE ; CASP8
    Abstract: Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASPIO rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1610-6)
    Type of Publication: Journal article published
    PubMed ID: 19423537
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  • 15
    Keywords: CANCER ; GROWTH ; PROSTATE ; COMMON ; COHORT ; RISK ; GENE ; CARCINOGENESIS ; BIOMARKERS ; LINKAGE ; polymorphism ; POLYMORPHISMS ; VARIANTS ; BREAST ; hormone ; HEALTH ; AGE ; MEN ; prostate cancer ; PROSTATE-CANCER ; cancer risk ; LINKAGE DISEQUILIBRIUM ; GERMLINE ; POSTMENOPAUSAL WOMEN ; SINGLE ; VARIANT ; DETERMINANTS ; prospective studies ; GROWTH-FACTOR-I ; LEVEL ; biomarker ; EPIDEMIOLOGIC EVIDENCE ; HAPLOTYPE ; HAPLOTYPES ; LOCUS ; USA ; HORMONES ; HORMONE LEVELS ; TESTOSTERONE ; prospective ; prospective study ; STEROID-HORMONES ; JAPANESE ; UNIT ; cancer research ; CANCER-RISK ; ESTROGEN-LEVELS ; MULTIETHNIC COHORT ; ANDROGEN ; COMMON VARIANT ; SEX-HORMONES ; JAPANESE POPULATION ; androgens ; NONCARRIERS ; FREE TESTOSTERONE ; SERUM ANDROGENS ; CONSORTIUM ; 3 ; Genetic ; genetic variation ; COMMON VARIANTS ; GENE VARIANT ; ALLELIC VARIANTS ; ANDROGEN BIOSYNTHESIS ; UNRELATED INDIVIDUALS
    Abstract: Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterized variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nuclecitide polymorphisms (htSNP) that efficiently predict common variants in U.S. and Europe-an whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs; in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5% to 10% difference in estradiol concentrations in men [association per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 1 x 10(-5)], and with inverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterized by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2734-44)
    Type of Publication: Journal article published
    PubMed ID: 19789370
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  • 16
    Keywords: CANCER ; COHORT ; DNA adducts ; POPULATION ; RISK ; GENE ; GENES ; PROTEIN ; PATIENT ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; REPAIR ; cancer risk ; familial risk ; SERIES ; EXCISION-REPAIR ; SINGLE ; RE ; BRCA2 ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; XPD ; GENOTYPE ; HAPLOTYPE ; invasive breast cancer
    Abstract: A substantial proportion of the familial risk of breast cancer may be due to genetic variants, each contributing a small effect. The protein encoded by ERCC2 is a key enzyme involved in nucleotide excision repair, in which gene defects could lead to cancer prone syndromes such as Xeroderma pigmentosum D. We have examined the association between single nucleotide polymorphisms in the ERCC2 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3,634 patients and of 3,340 controls. None of the three single nucleotide polymorphisms were significantly associated with the incidence of breast cancer
    Type of Publication: Journal article published
    PubMed ID: 16030124
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  • 17
    Keywords: CANCER ; RISK ; ASSOCIATION ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; VARIANT ; SNPs
    Abstract: The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 -202 C --〉 A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3' UTR A --〉 G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9-15 studies, comprising 11,391-18,290 cases and 14,753-22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.: 0.62-0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P(trend) = 1.1 x 10(-7)) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02-1.13) and 1.16 (95% c.i.: 1.08-1.25), respectively; P(trend) = 2.8 x 10(-5)). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies
    Type of Publication: Journal article published
    PubMed ID: 17293864
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  • 18
    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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