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  • Health Reference Center Academic (Gale)  (10)
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  • 1
    Language: English
    In: Environmental Geochemistry and Health, 2017, Vol.39(2), pp.331-344
    Description: Central European floodplain soils are often contaminated with potentially toxic metals. The prediction of their aqueous concentrations is a prerequisite for an assessment of environmental concerns. We tested the aqueous concentrations of cadmium (Cd), copper (Cu), nickel (Ni), lead (Pb) and zinc (Zn) derived from multi-surface adsorption modelling (on hydrous iron, aluminum and manganese oxides, clay and soil organic matter) against those analyzed in situ in the soil solution of four horizons of floodplain soils at the Elbe River, Germany. The input data for the reactive metals were derived from a seven-step sequential extraction scheme or from extraction with 0.43 M nitric acid (HNO 3 ) and evaluated in four modelling scenarios. In all scenarios, measured and modelled concentrations were positively related, except partially for Pb. Close reproduction of the measured data was obtained using measured data of accompanying cations and anions together with amounts of reactive metals from both the sequential extraction or from 0.43 M HNO 3 extraction, except for Cu, which was often strongly overestimated, and partially Cd. We recommend extraction with 0.43 M HNO 3 to quantify reactive metals in soil because the modelling results were metal-specific with better or equal results using the single extractant, the application of which is also less laborious. Approximations of ion concentrations and water contents yielded similar results. Modelled solid-phase speciation of metals varied with pH and differed from that from sequential extraction. Multi-surface modelling may be an effective tool to predict both aqueous concentrations and solid-phase speciation of metals in soil.
    Keywords: Multi-surface modelling ; Metals ; Soil contamination ; Sequential extraction ; Fluvisol
    ISSN: 0269-4042
    E-ISSN: 1573-2983
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  • 2
    In: Rapid Communications in Mass Spectrometry, 15 June 2018, Vol.32(11), pp.851-861
    Description: Rationale In contaminated soil, copper (Cu) is commonly distributed among various very small particles. To enlighten the qualitative distribution of Cu in a contaminated Technosol (a soil developed from deposited technogenic material) on the sub‐micron scale, we used nano‐scale secondary ion mass spectrometry...
    Keywords: Digital Imaging ; Mass Spectrometry ; Soil Contamination ; Contaminants ; Ions ; Spatial Smoothing ; Spectroscopy ; Copper ; Scientific Imaging ; Soil Contamination ; Image Processing ; Solid Phases ; Secondary Ion Mass Spectrometry;
    ISSN: 0951-4198
    E-ISSN: 1097-0231
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  • 3
    Language: English
    In: Nature, 11/2017, Vol.551(7678), pp.92-94
    Description: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P 〈 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
    Keywords: Ancestry ; Cancer ; Gene ; Genetic Variation ; Genome ; Health Risk ; Heritability ; Polymorphism ; Tumor ; Europe ; Far East ; Medicin Och Hälsovetenskap ; Medicinska Och Farmaceutiska Grundvetenskaper ; Medicinsk Genetik ; Medical And Health Sciences ; Basic Medicine ; Medical Genetics ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi ; Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 4
    Language: English
    In: Nature genetics, July 2018, Vol.50(7), pp.968-978
    Description: The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P 〈 5.82 × 10, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
    Keywords: Breast Neoplasms -- Genetics
    ISSN: 10614036
    E-ISSN: 1546-1718
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  • 5
    In: Journal Of The National Cancer Institute, 2016, Vol. 108(2)
    Description: Background: The K3326X variant in BRCA2 ( BRCA2 *c.9976A〉T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.
    Keywords: Brca Mutations – Health Aspects ; Codons – Properties ; Disease Susceptibility – Genetic Aspects ; Carcinogenesis – Genetic Aspects;
    ISSN: 0027-8874
    E-ISSN: 1460-2105
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  • 6
    In: Nature Genetics, 2016
    Description: We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor alpha ) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER super(+) or ER super(-)) and human ERBB2 (HER2 super(+) or HER2 super(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER super(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
    Keywords: Enhancers ; Erbb-2 Protein ; Mammography ; Breast Cancer ; Tumors ; Estrogen Receptors ; Human Genetics ; Protein-Nucleic Acids Association;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 7
    In: Nature Genetics, 2015, Vol.47(2), p.164
    Description: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1 p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P 〈 5 x [10.sup.-8]. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
    Keywords: Ovarian Cancer – Genetic Aspects ; Quantitative Trait Loci – Identification and Classification ; Quantitative Trait Loci – Health Aspects;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 8
    Language: English
    In: Gaudet, Mia M., Karoline B. Kuchenbaecker, Joseph Vijai, Robert J. Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, et al. 2013. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk. PLoS Genetics 9(3): e1003173.
    Description: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
    Keywords: Biology ; Genetics ; Cancer Genetics ; Genome-Wide Association Studies
    ISSN: 1553-7390
    ISSN: 1553-7404
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  • 9
    Language: English
    In: Breast Cancer Research, 2016, Vol. 18
    Description: Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P 〈 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P 〈 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
    Keywords: Fine-Scale Mapping ; Genetic Risk Factor ; Pthlh ; Ccdc91 ; Breast Cancer ; Brac1 Mutation Carriers ; Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi ; Medical And Health Sciences ; Basic Medicine ; Medical Genetics ; Medicin Och Hälsovetenskap ; Medicinska Och Farmaceutiska Grundvetenskaper ; Medicinsk Genetik
    ISSN: 1465-5411
    E-ISSN: 1465542X
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  • 10
    Language: English
    In: The American Journal of Human Genetics, 03 January 2019, Vol.104(1), pp.21-34
    Description: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
    Keywords: Breast ; Cancer ; Risk ; Polygenic ; Stratification ; Genetic ; Epidemiology ; Screening ; Prediction ; Score ; Biology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
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