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  • 1
    Keywords: WOMEN ; HEREDITARY ; HIGH-RISK ; BREAST ; BREAST-CANCER ; breast cancer ; RISK ; screening ; CANCER ; HEREDITARY BREAST ; PROGRESS
    Type of Publication: Book chapter
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  • 2
    Keywords: CANCER ; BLOOD ; DISEASE ; RISK ; GENE ; PROTEIN ; SAMPLES ; PATIENT ; DNA ; FAMILY ; FREQUENCY ; BREAST ; BREAST-CANCER ; family history ; OVARIAN-CANCER ; WOMEN ; MUTATION ; MUTATIONS ; PREVALENCE ; BRCA1/2 ; BRCA2 MUTATIONS ; early-onset breast cancer ; German population ; germline mutations ; POPULATION-BASED SAMPLE
    Abstract: This study was undertaken to investigate the prevalence of BRCA1 and BRCA2 germline mutations in 91 German patients unselected for family history, who were diagnosed with breast cancer before the age of 41 years. Clinical information and blood samples were obtained from all patients. A comprehensive BRCA1 and BRCA2 mutational analysis was performed using the protein truncation assay and single-strand conformational polymorphism analysis followed by DNA sequencing of variant signals detected by these assays. Five different deleterious germline mutations including four frameshift mutations and one missense mutation were identified, three in BRCA1 (3.3%) and two mutations (2.2%) in BRCA2. Both BRCA2 mutations are novel and might be specific for the German population. An additional BRCA1 missense mutation previously described and classified as an unknown variant was found. This mutation was also detected in two breast cancer patients of family P 328 and not in 140 healthy controls suggesting that it is disease associated. In addition, one common polymorphism and five novel intronic sequence variants with unknown significance were found. Our findings show that mutations in BRCA1 and BRCA2 may contribute similarly to early-onset breast cancer in Germany. Given current constraints on health-care resources, these results support the notion that BRCA1 and BRCA2 mutation screening may have the strongest impact on health-care when targeted to high- risk populations
    Type of Publication: Journal article published
    PubMed ID: 12774040
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  • 3
    Keywords: CANCER ; tumor ; carcinoma ; CLASSIFICATION ; COHORT ; DISTINCT ; GENE ; GENES ; TUMORS ; PATIENT ; prognosis ; treatment ; FREQUENCY ; SUSCEPTIBILITY ; BREAST ; DESIGN ; AGE ; BRCA1 ; OVARIAN-CANCER ; WOMEN ; MUTATION ; REPRODUCIBILITY ; p53 ; MUTATIONS ; MORPHOLOGY ; adenocarcinoma ; CARRIERS ; CANCER-RESEARCH ; SERIES ; POOR-PROGNOSIS ; FEATURES ; BRCA2 GENE ; GRADE ; MUTATION CARRIERS ; GERM-LINE MUTATIONS ; FAMILIAL BREAST-CANCER
    Abstract: Purpose: Germline mutations in the BRCA1 and BRCA2 genes confer increased susceptibility to ovarian cancer. There is evidence that tumors in carriers may exhibit a distinct distribution of pathological features, but previous studies on the pathology of such tumors have been small. Our aim was to evaluate the morphologies and immunophenotypes in a large cohort of patients with familial ovarian cancer.Experimental Design: We performed a systematic review of ovarian tumors from 178 BRCA1 mutation carriers, 29 BRCA2 mutation carriers, and 235 controls with a similar age distribution. Tumors were evaluated by four pathologists blinded to mutation status. Both morphological features and immunochemical staining for p53 and HER2 were evaluated.Results: Tumors in BRCA1 mutation carriers were more likely than tumors in age-matched controls to be invasive serous adenocarcinomas (odds ratio, 1.84; 95% confidence interval, 1.21-2.79) and unlikely to be borderline or mucinous tumors. Tumors in BRCA1 carriers were of higher grade (P 〈 0.0001), had a higher percentage solid component (P 0.001), and were more likely to stain strongly for p53 (P = 0.018). The distribution of pathological features in BRCA2 carriers was similar to that in BRCA1 carriers.Conclusions: Use of pathological features can substantially improve the targeting of predictive genetic testing. Results also suggest that BRCA1 and BRCA2 tumors are relatively. aggressive and may be expected to have poor prognosis, although this may be treatment dependent
    Type of Publication: Journal article published
    PubMed ID: 15073127
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  • 4
    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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  • 5
    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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  • 6
    Keywords: CANCER ; Germany ; DISEASE ; RISK ; GENE ; GENOME ; RNA ; ASSOCIATION ; polymorphism ; BREAST ; breast cancer ; BREAST-CANCER ; NO ; OVARIAN-CANCER ; WOMEN ; MUTATION ; cancer risk ; REGION ; genotyping ; MUTATIONS ; case-control studies ; ONCOLOGY ; case-control study ; REGRESSION ; RE ; FAMILIES ; PENETRANCE ; analysis ; methods ; SUPPRESSOR ; GENOTYPE ; BRCA1 MUTATION CARRIERS ; BIRTH ; CANCER-RISK ; FRAGMENT ; ENGLAND ; comparison ; Rb ; UNTRANSLATED REGION
    Abstract: Background: The variable penetrance of ovarian cancer in BRCA1 mutation carriers suggests that other genetic or environmental factors modify disease risk. The C to T transition in the 3' untranslated region of the prohibitin ( PHB) gene alters mRNA function and has recently been shown to be associated with hereditary breast cancer risk in Polish women harbouring BRCA1 mutations. Methods: To investigate whether the PHB 3' UTR polymorphism also modifies hereditary ovarian cancer risk, we performed a case-control study among Polish women carrying one of the three common founder mutations (5382insC, 300 T 〉 G, 4154delA) including 127 ovarian cases and 127 unaffected controls who had both breasts and ovaries intact. Controls were matched to cases by year of birth and BRCA1 mutation. Genotyping analysis was performed using PCR-based restriction fragment length polymorphism analysis. Odds ratios ( OR) were calculated using conditional and penalized univariable and multivariable logistic regression. Results: A comparison of the genotype frequencies between cases and controls revealed no association of the PHB 3'UTR_CT+TT genotypes with ovarian cancer risk ( ORadj 1.34; 95% CI, 0.59-3.11). Conclusion: Our data suggest that the PHB 3' UTR polymorphism does not modify ovarian cancer risk in women carrying one of the three Polish BRCA1 founder mutations
    Type of Publication: Journal article published
    PubMed ID: 18397521
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  • 7
    Keywords: CANCER ; MODEL ; RISK ; FAMILY ; SUSCEPTIBILITY ; breast cancer ; BREAST-CANCER ; BRCA1 ; WOMEN ; MUTATIONS ; MANAGEMENT ; VARIANT ; CHEK2 ; ALLELES ; ATM ; GENOME-WIDE ASSOCIATION ; BOADICEA MODEL ; PALB2
    Abstract: If breast cancers arise independently in each breast the odds ratio (OR) for bilateral breast cancer for carriers of CHEK2*11.00delC should be similar to 5.5, the square of the reported OR for a first primary (OR, 2.34). In the subset of bilateral cases with one or more affected relatives, the predicted carrier OR should be similar to 9. We have tested these predictions in a pooled set of 1,828 cases with 2 primaries and 7,030 controls from 8 studies. The second primary OR for CHEK2*1100delC carriers was 6.43 (95% confidence interval, 4.339.56; P 〈 0.0001), significantly greater than the published estimate for a first primary (P 〈 0.001) but consistent with its square. The predicted increase in carrier OR with increasing numbers of affected relatives was seen using bilateral cases from the UK (P-trend = 0.0003) and Finland (P-trend = 0.37), although not using those from the Netherlands and Russia (P = 0.001 for heterogeneity between countries). Based on a standard genetic model, we predict lifetime risks for CHEK2*1100delC carrier and noncarrier daughters of bilateral breast cancer cases of 37% and 18%, respectively. Our results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2*1100delC carrier status. This and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk. Before such predictions are accepted by clinical geneticists, however, further population-based evidence is needed on the effect of CHEK2*1100delC and other moderate penetrance alleles in women with a family history of breast cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(1):230-4)
    Type of Publication: Journal article published
    PubMed ID: 19124502
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  • 8
    Keywords: RECEPTOR ; CANCER ; CELLS ; GROWTH ; SURVIVAL ; tumor ; BLOOD ; Germany ; THERAPY ; DIAGNOSIS ; FOLLOW-UP ; COHORT ; DISEASE ; MORTALITY ; RISK ; METABOLISM ; TISSUE ; TIME ; PATIENT ; DNA ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; STAGE ; hormone ; DESIGN ; WOMEN ; RATES ; chemotherapy ; METABOLIC-ACTIVATION ; GENOTYPES ; RECURRENCE ; US ; OUTCOMES ; ADJUVANT ; RANDOMIZED-TRIAL ; METABOLITE ; POSTMENOPAUSAL WOMEN ; VARIANT ; THERAPIES ; ALLELES ; ALL-CAUSE MORTALITY ; USA ; INCREASED RISK ; outcome ; STATE ; CONFIDENCE ; ENZYME-ACTIVITY ; CYTOCHROME-P450 ; CYTOCHROME-P450 2D6 ; ENDOCRINE THERAPY ; RECEIVING ADJUVANT TAMOXIFEN
    Abstract: Context The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor-positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme. Objective To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen. Design, Setting, and Patients Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism. Main Outcome Measures Time to recurrence, event-free survival, disease-free survival, and overall survival. Results Median follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51). Conclusion Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes. JAMA. 2009; 302(13): 1429-1436
    Type of Publication: Journal article published
    PubMed ID: 19809024
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  • 9
    Keywords: OVARIAN-CANCER ; WOMEN ; chemotherapy ; PHENOTYPE ; PREVALENCE ; CANCER PATIENTS ; ESTROGEN-RECEPTOR ; 185DELAG ; HER-2 ; GERMLINE MUTATION
    Abstract: Metaplastic breast carcinoma (MBC) is a relatively rare subtype of breast cancer that encompasses a pathologically heterogeneous group of tumors. Pathogenic germ line mutations in the major breast cancer susceptibility genes BRCA1 and BRCA2 genes have been rarely found or described in MBC. We report the identification of the BRCA1 185delAG mutation in a 22-year-old Pakistani woman with triple-negative MBC that showed biphasic morphological features, including sarcomatous and malignant epithelial components. A comprehensive description of the clinical, histopathological, morphological, and immunohistochemical features of the tumor and the patient's treatment course is presented.
    Type of Publication: Journal article published
    PubMed ID: 21723046
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  • 10
    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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