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  • 1
    Keywords: CANCER ; Germany ; DISEASE ; POPULATION ; RISK ; GENOME ; PATIENT ; ASSOCIATION ; FREQUENCY ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; BRCA1 ; WOMEN ; MUTATION ; REPAIR ; cancer risk ; MUTATIONS ; DNA-DAMAGE ; case-control studies ; RISK ASSESSMENT ; PREVALENCE ; BRCA1/2 ; EUROPE ; ONCOLOGY ; case control study ; case-control study ; ASSOCIATIONS ; RE ; ALLELE ; case control studies ; NEED ; EUROPEAN POPULATIONS ; breast cancer patients selected for family history and age ; CHEK2 GENE ; CHEK2*1100delC variant ; population-based study
    Abstract: CHEK2*1100delC is associated with a twofold increased breast cancer risk. This was shown in a collaborative analysis of European populations, but not in other populations from Europe and the US. Accordingly, there is a need to clarify the role of CHEK2*1100delC in breast cancer. We established its prevalence in two German populations GENICA (Northrhine-Westphalia, it = 724) and KORA (Bavaria, n = 600) and in women with breast cancer. The latter included cases (n = 688) from the GENICA breast cancer case-control study, patients with early-onset breast cancer (n = 86) and patients with familial breast cancer (n = 71). The latter patient groups were previously investigated for BRCA1/2-mutations and tested negative. Mutation analysis was performed by combined PCR/DHPLC methodology. CHEK2*1100delC was found in 0.9% of GENICA controls and was absent in the KORA controls indicating a significant difference between the two populations (P = 0.03). The frequency of CHEK2*1100delC in age-matched cases of the GENICA collection was 0.8% and thus not different from controls (OR 0.88, 95% CI 0.21-3.50). In patients with early-onset disease CHEK2*1100delC was found at a frequency of 2.3% referring to an increased breast cancer risk of 2.56 (95% Cl 0.25-14.58). In patients with familial disease the frequency was 1.4% referring to an increased risk of 1.53 (95% CI 0.03-12.93). Our data showed variations in CHEK2*1100delC prevalence within German populations suggesting possible inaccuracies in breast cancer risk assessments from non population-based studies. In patients with a high-risk profile however, CHEK2*1100delC was indicative for this risk and highest for early-onset breast cancer. (c) 2005 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16239104
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  • 2
    Keywords: CANCER ; Germany ; THERAPY ; DENSITY ; COHORT ; HISTORY ; RISK ; FAMILY ; ASSOCIATION ; BREAST ; breast cancer ; BREAST-CANCER ; TRIAL ; family history ; WOMEN ; HORMONE REPLACEMENT THERAPY ; cancer risk ; MAMMOGRAPHY ; case-control studies ; case-control study ; population-based case-control study ; HORMONE-REPLACEMENT THERAPY ; case control studies ; INTERVAL ; SCREEN ; FAMILY-HISTORY ; ESTROGEN PLUS PROGESTIN ; HEALTHY POSTMENOPAUSAL WOMEN ; breast cancer risks ; family history of cancer ; HRT USE ; risk-modifying factors
    Abstract: Objectives: Hormone-replacement therapy (HRT) is an established risk factor for breast cancer. HRT users are different from non-users with respect to socio-economic and other characteristics. There may be women where the HRT-related risk could be modulated by other factors. Methods: We conducted a population-based case-control study with 688 breast cancer cases and 724 controls to characterize HRT users and to estimate odds ratios (OR) and 95% confidence intervals (CI) for HRT use and potentially risk modifying factors. Results: In women aged 50 years and older, 58% of controls and 61% of cases ever used HRT. Among women in natural menopause, HRT use for 10 years and more years was associated with an increased breast cancer risk (OR 1.79, 95% CI, 1.12-2.87), but not among women in surgical menopause (OR 0.61, 95% CI, 0.09-4.17). In the subgroup of women with a positive family history of breast cancer, each year of HRT use increased the risk by 1.22 (95% CI, 1.02-1.47). Another subgroup comprised women with at least 10 diagnostic mammograms (OR 4.04, 95% CI, 1.10-14.81 for using HRT 10 or more years). Conclusions: Long-term HRT use was associated with a breast cancer risk in women with natural menopause. Our findings suggest that this risk may be increased in women with a positive family history of breast cancer and in women who received frequent diagnostic mammographic screens
    Type of Publication: Journal article published
    PubMed ID: 16151884
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  • 3
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; tumor ; CELL ; Germany ; THERAPY ; DISEASE ; HISTORY ; RISK ; GENE ; GENES ; COMPLEX ; COMPLEXES ; MECHANISM ; FAMILY ; mechanisms ; ASSOCIATION ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; NUMBER ; STRESS ; ovarian cancer ; OVARIAN-CANCER ; smoking ; ORAL-CONTRACEPTIVES ; OXIDATIVE STRESS ; body mass index ; glutathione-S-transferase ; PHASE-II ; ONCOLOGY ; ASSOCIATIONS ; LIGHT ; PHASE ; GENOTYPE ; FAMILY-HISTORY ; GLUTATHIONE S-TRANSFERASES ; BODY-MASS ; breast cancer risk ; COLLECTION ; hormone therapy ; Metabolizing enzymes ; METABOLIZING GENES ; GSTs
    Abstract: Breast cancer is a complex disease and in recent years a number of breast cancer susceptibility genes have been identified, but the role of low penetrance susceptibility genes has not been completely resolved. Glutathione S-transferases (GSTs) are phase II xenobiotic metabolizing enzymes involved in the detoxification of chemical carcinogens and environmental pollutants and play an important role in cell defense mechanisms against oxidative stress. They have been in the spot light for the investigation of a potential association with breast cancer risk but so far, sparse or even no data for a potential contribution of GSTA2, GSTM2, GSTO, and GSTZ to breast cancer risk are available. We genotyped GSTA2_448_C 〉 G (rs2180314), GSTA2_742_A 〉 C (rs6577), GSTM2_-832_T 〉 C (rs638820), GSTO1_-1242_G 〉 A (rs2164624), GSTO1_419_A 〉 C (rs4925), GSTO2_-183_A 〉 G (rs2297 235), GSTO2_342_A 〉 G (rs156697), GSTZ1_-4378_A 〉 G (rs1046428), and GSTZ1_94_G 〉 A (rs3177427) by MAL DI-TOF MS in the German GENICA breast cancer case-control collection of 1021 cases and 1015 controls and performed breast cancer risk association in general and with respect to the stratifications: menopausal status, family history of breast or ovarian cancer, use of oral contraceptives, use of hormone therapy, body mass index, and smoking as well as histopathological tumor characteristics including hormone receptor status, grade, histology, and node status. We did not observe any breast cancer risk associations and conclude that it is unlikely that glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 participate in breast cancer susceptibility
    Type of Publication: Journal article published
    PubMed ID: 19859803
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  • 4
    Keywords: APOPTOSIS ; CANCER ; RISK ; METABOLISM ; polymorphism ; breast cancer ; WOMEN ; RANDOMIZED CONTROLLED-TRIAL ; ESTROGEN PLUS PROGESTIN ; CYTOCHROME-P450 ; GENE VARIANT ; 2C19
    Type of Publication: Journal article published
    PubMed ID: 22037784
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  • 5
    Keywords: RISK ; ASSOCIATION ; METAANALYSIS ; CHINESE WOMEN ; RECEPTOR STATUS ; MELATONIN ; SHIFT-WORK ; GERMAN GENICA ; CLOCK GENES ; IJAZ S
    Abstract: Objectives: The role of genetic variants and environmental factors in breast cancer etiology has been intensively studied in the last decades. Gene-environment interactions are now increasingly being investigated to gain more insights into the development of breast cancer, specific subtypes, and therapeutics. Recently, night shift work that involves circadian disruption has gained rising interest as a potential non-genetic breast cancer risk factor. Here, we analyzed genetic polymorphisms in genes of cellular clocks, melatonin biosynthesis and signaling and their association with breast cancer as well as gene-gene and gene-night work interactions in a German case-control study on breast cancer. Methods: GENICA is a population-based case-control study on breast cancer conducted in the Greater Region of Bonn. Associations between seven polymorphisms in circadian genes (CLOCK, NPAS2, ARTNL, PER2 and CRY2), genes of melatonin biosynthesis and signaling (AANAT and MTNR1B) and breast cancer were analyzed with conditional logistic regression models, adjusted for potential confounders for 1022 cases and 1014 controls. Detailed shift-work information was documented for 857 breast cancer cases and 892 controls. Gene-gene and gene-shiftwork interactions were analyzed using model-based multifactor dimensionality reduction (mbMDR). Results: For combined heterozygotes and rare homozygotes a slightly elevated breast cancer risk was found for rs8150 in gene AANAT (OR 1.17; 95% CI 1.01-1.36), and a reduced risk for rs3816358 in gene ARNTL (OR 0.82; 95% CI 0.69-0.97) in the complete study population. In the subgroup of shift workers, rare homozygotes for rs10462028 in the CLOCK gene had an elevated risk of breast cancer (OR for AA vs. GG: 3.53; 95% CI 1.09-11.42). Shift work and CLOCK gene interactions were observed in the two-way interaction analysis. In addition, gene-shiftwork interactions were detected for MTNR1B with NPAS2 and ARNTL. Conclusions: In conclusion, the results of our population-based case-control study support a putative role of the CLOCK gene in the development of breast cancer in shift workers. In addition, higher order interaction analyses suggest a potential relevance of MTNR1B with the key transcriptional factor NPAS2 with ARNTL. Hence, in the context of circadian disruption, multivariable models should be preferred that consider a wide range of polymorphisms, e.g. that may influence chronotype or light sensitivity. The investigation of these interactions in larger studies is needed.
    Type of Publication: Journal article published
    PubMed ID: 25229211
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  • 6
    Keywords: APOPTOSIS ; CANCER ; CELL ; Germany ; LUNG-CANCER ; DISEASE ; POPULATION ; RISK ; ENZYMES ; GENE ; transcription ; DNA ; SKIN ; cell cycle ; CELL-CYCLE ; CYCLE ; FREQUENCY ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; IDENTIFICATION ; WOMEN ; DNA-REPAIR ; MUTATION ; REPAIR ; smoking ; SPECTROMETRY ; LINE ; BLADDER-CANCER ; cancer risk ; REGION ; GENOTYPES ; MASS-SPECTROMETRY ; MUTATIONS ; ADDUCTS ; CARRIERS ; case-control studies ; CANCER-RESEARCH ; GERM-LINE ; CYCLE CONTROL ; EXCISION-REPAIR ; DNA-REPAIR GENES ; SKIN-CANCER ; MASSES ; POTENT ; case control study ; case-control study ; VARIANT ; CANCER SUSCEPTIBILITY ; LYS751GLN POLYMORPHISM ; XPD ; XPD POLYMORPHISMS
    Abstract: The polygenic concept of breast cancer susceptibility calls for the identification of genetic variants that contribute to breast cancer risk. Reduced DNA repair proficiencies in women with breast cancer pointed to a possible role of DNA repair enzymes in the risk to develop the disease. The nucleotide excision repair enzyme encoded by the excision repair cross-complementing group 2 gene ERCC2 (formerly XPD) known to cause skin cancer by germ line mutations has multiple regulatory cellular functions, including nucleotide excision repair, basal transcription, cell cycle control, and apoptosis. ERCC2 polymorphisms ERCC2_6540_G〉A (Asp(312)Asn) and ERCC2_18880_A〉C (Lys(751)Gln) within the coding region of this evolutionarily highly conserved gene have been of functional relevance and therefore are potential candidates to confer breast cancer susceptibility. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we analyzed genotype frequencies in constitutional DNA of study participants of a German case-control study that included 688 cases of incident breast cancer and 724 population-based, age-matched controls. We identified ERCC2_6540_GG (Asp(312)Asp) as an at-risk genotype [odds ratio (OR), 2.06; 95% confidence interval (95% CI), 1.39-3.07]. The ERCC2_6540_GG-associated breast cancer risk was even higher in women who were also carriers of the ERCC2_18880_CC (Gln(751)Gln) genotype (OR, 3.69; 95% CI, 1.76-7.74). We identified ERCC2_6540_G/ERCC2_18880_C (Asp(312)/Gln(751)) as the most potent risk-conferring haplotype (OR, 3.49; 95% CI, 2.30-5.28). To our knowledge, this is the first study assigning breast cancer risk to both the ERCC2 genotype encoding Asp(312)Asp and the haplotype encoding Asp(312)/Gln(751)
    Type of Publication: Journal article published
    PubMed ID: 15598761
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  • 7
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; tumor ; CELL ; FACTOR RECEPTOR ; Germany ; human ; GENE ; GENES ; TUMORS ; MECHANISM ; TRANSCRIPTION FACTOR ; prognosis ; mechanisms ; cell cycle ; CELL-CYCLE ; CYCLE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; AMPLIFICATION ; mass spectrometry ; cancer risk ; MASS-SPECTROMETRY ; case-control studies ; OVEREXPRESSION ; EPIDERMAL-GROWTH-FACTOR ; CYCLIN D1 ; case-control study ; REGRESSION ; MS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; GENOTYPE ; ADJUVANT CHEMOTHERAPY ; HER2 ; USA ; LOCI ; TRASTUZUMAB ; CCND1 ; breast tumor ; CCND3 ; E2F2 ; HER2 status
    Abstract: Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast tumors is associated with bad prognosis. Therefore, it is highly relevant to further improve understanding of the regulatory mechanisms of HER2 expression. In addition to gene amplification, transcriptional regulation plays a crucial role in HER2 overexpression. In this study, we analyzed 3 polymorphisms E2F2_-5368-A〉G, CCND1-870-A〉G and CCND3_-677_C〉T located in genes involved in cell cycle regulation in the GENICA population-based and age-matched breast cancer case-control study from Germany. We genotyped 1,021 cases and 1,015 controls by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Statistical analyses were performed by conditional logistic regression. We observed no differences in genotype frequencies between breast cancer cases and controls. Subgroup analysis showed associations between carriers of the E2F2_-5368_G allele (OR: 0.60, 95% CI: 0.42-0.85), carriers of the (C) over bar CND (1) over bar _870 G allele (OR: 0.66, 95% CI: 0.45-0.96) and carriers of the -CC (N) over bar D3_-677_T allele (OR: 1.72, 95% CI: 1.20-2.49) and HER2 expression in breast tumors. This finding points to an association of an increased expression of these cell cycle regulators with lower expression of HER2. An explanation for this observation might be that low expression of E2F2, CCND1 and CCND3 decrease levels of factors down-regulating HER2. We conclude that the analyzed polymorphisms located in E2F2, CCND1 and CCAID3 are potential markers for HER2 status of breast tumors. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 19142864
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  • 8
    Keywords: CANCER ; EXPRESSION ; COMBINATION ; Germany ; THERAPY ; LONG-TERM ; RISK ; DRUG ; METABOLISM ; IMPACT ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; WOMEN ; mass spectrometry ; cancer risk ; MASS-SPECTROMETRY ; VARIABILITY ; PHENOTYPE ; POSTMENOPAUSAL WOMEN ; MATRIX ; REGRESSION ; THERAPIES ; HORMONE-REPLACEMENT THERAPY ; SUBSTRATE ; ESTROGEN ; TESTS ; USA ; population-based ; CANCER-RISK ; hormone therapy ; ASSISTED-LASER-DESORPTION/IONIZATION ; Genetic ; CURE RATES ; CYP2C19 ; CYTOCHROME-P450 ; DRUG RESPONSE ; GENE VARIANT ; PEPTIC-ULCER ; PROTON PUMP INHIBITORS
    Abstract: Cytochrome P450 2C19 (CYP2C19) plays an important role in the metabolism of xenobiotics and drugs and contributes to the catabolism of endogenous substrates like estradiol. Genetic variability impacts expression and activity of CYP2C19 and therefore can influence catabolism of estrogens. In the present study we analyzed the association of three polymorphisms of CYP2C19 namely CYP2C19*2 (CYP2C19_681_G 〉 A, rs4244285), CYP2C19*3 (CYP2C19_636_G 〉 A, rs57081121) and CYP2C19*17 (CYP2C19_-806_C 〉 T, rs12248560), with breast cancer susceptibility. We genotyped 1,015 breast cancer cases and 1,021 age-matched, population-based controls of the German GENICA study by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Risk estimates were calculated by logistic regression. All tests were two-sided. We observed a decreased breast cancer risk for carriers of the CYP2C19*17 allele (OR 0.77, 95% CI: 0.65-0.93; P = 0.005). In subgroup analysis we observed a significant decreased breast cancer risk for women using hormone therapy for ten years or longer who were carriers of the CYP2C19*17 allele (OR 0.57, 95% CI: 0.39-0.83; P = 0.003). Since CYP2C19*17 defines an ultra rapid metabolizer phenotype we suggest that an increased catabolism of estrogens by CYP2C19 may lead to decreased estrogen levels and therefore reduces breast cancer risk. This protective effect seems to be stronger in combination with long-term intake of supplemental estrogens during hormone therapy
    Type of Publication: Journal article published
    PubMed ID: 18521743
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  • 9
    Abstract: Long-term hormone therapy (HT) is a recognized risk factor for postmenopausal breast cancer. Elevated steroid hormone levels play a critical role in breast carcinogenesis and this may be contributed by the efficiency of hormone biosynthesis. Within this context, genetic polymorphisms related to steroid hormone biosynthesis may modify HT-associated postmenopausal breast cancer risk. CYP17 is a key player of this pathway and the CYP17A1_-34_T 〉 C polymorphism has been suggested to affect breast cancer risk in women using long-term HT. We genotyped 13 polymorphisms of seven genes of the steroid hormone biosynthesis pathway in 3,149 postmenopausal breast cancer patients and 5,489 age-matched controls from Germany. We observed a significant interaction of CYP17A1_-34_T 〉 C and HT use on breast cancer risk in a co-dominant model (P (interaction) = 0.007). Current users of estrogen monotherapy showed a significantly increased risk for duration of use per 5-year increment when they were carriers of the CYP17A1_-34_TC genotype (OR 1.13, 95% CI: 1.04-1.23 per 5 years of use). We conclude that CYP17A1_-34_T 〉 C may be part of the genetic background to contribute to postmenopausal breast cancer risk in women using estrogen monotherapy.
    Type of Publication: Journal article published
    PubMed ID: 19672705
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  • 10
    Abstract: Menopausal hormone therapy (HT) is associated with increased breast cancer risk among postmenopausal women. Nuclear receptors are involved in steroid hormone- and xenobiotic-mediated signal transduction playing a crucial role in regulating gene expression. Therefore, variations within these genes may influence HT-associated breast cancer risk. We investigated 3,149 postmenopausal breast cancer patients and 5,489 controls from 2 German population-based case-control studies. Thirty-three polymorphisms selected on the basis of known or putative functional relevance located in ESR1, ESR2, PGR, PXR and AR were genotyped. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen-progestagen therapy and of estrogen monotherapy with regard to breast cancer risk assuming log-additive and codominant modes of inheritance. We observed an increased risk for women carrying short AR_(CAG) alleles of 〈22 repeats associated with combined estrogen-progestagen therapy compared with those with long alleles (〉 or =22 repeats) (p(interaction) = 0.03). Additionally, risk associated with combination therapy use was significantly modified by 2 PXR polymorphisms with reduction of risk effects in carriers of the minor PXR_rs6785049_G and PXR_rs1054191_A alleles (p(interaction) = 0.04 and 0.05, respectively). Variants in both ESR1 and ESR2 modified risk associated with estrogen monotherapy use. Higher risk were observed in homozygotes for the major ESR1_rs910416_T allele (p(interaction) 〈 0.01) and in homozygotes for the minor ESR2_rs1271572_T, major ESR2_rs4986938_G and minor ESR2_rs928554_G alleles (p(interaction) = 0.02, 0.05, 0.02, respectively). Risk effect modification by ESR1_rs910416 and AR_(CAG)n polymorphisms remained significant after correction for multiple testing. We conclude that genetic variants in nuclear receptor genes may modify HT-associated postmenopausal breast cancer risk.
    Type of Publication: Journal article published
    PubMed ID: 19739075
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