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Sökning: WFRF:(Ahearn Thomas U)

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  • [1]234567...9Nästa
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1.
  • Zhan, Haoyu, et al. (författare)
  • Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses
  • 2020
  • Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 52:6, s. 572-
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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2.
  • Morra, Anna, et al. (författare)
  • Breast Cancer Risk Factors and Survival by Tumor Subtype : Pooled Analyses from the Breast Cancer Association Consortium
  • 2021
  • Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 30:4, s. 623-642
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (P-adj > 0.30). The strongest associations were between all-cause mortality and BMI >= 30 versus 18.5-25 kg/m(2) [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age >= 30 years versus < 20 years at first pregnancy [0.79 (0.72-0.86)]; >0-< 5 years versus >= 10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
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3.
  • Liu, Jingjing, et al. (författare)
  • Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk
  • 2020
  • Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
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4.
  • Dörk, Thilo, et al. (författare)
  • Two truncating variants in FANCC and breast cancer risk
  • 2019
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95% CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
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5.
  • Coignard, Juliette, et al. (författare)
  • A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
  • 2021
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723 .- 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P<10(-8), at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers. Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.
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6.
  • Kapoor, Pooja Middha, et al. (författare)
  • Combined associations of a polygenic risk score and classical risk factors with breast cancer risk
  • 2021
  • Ingår i: Journal of the National Cancer Institute. - 0027-8874 .- 1460-2105. ; 113:3, s. 329-337
  • Tidskriftsartikel (refereegranskat)abstract
    • We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer. 
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7.
  • Agarwal, Jessica, et al. (författare)
  • Acceleration of individual, decimetre-sized aggregates in the lower coma of comet 67P/Churyumov-Gerasimenko
  • 2016
  • Ingår i: Monthly notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 462, s. S78-S88
  • Tidskriftsartikel (refereegranskat)abstract
    • We present observations of decimetre-sized, likely ice-containing aggregates ejected from a confined region on the surface of comet 67P/Churyumov-Gerasimenko. The images were obtained with the narrow angle camera of the Optical, Spectroscopic, and Infrared Remote Imaging System on board the Rosetta spacecraft in 2016 January when the comet was at 2 au from the Sun outbound from perihelion. We measure the acceleration of individual aggregates through a 2 h image series. Approximately 50 per cent of the aggregates are accelerated away from the nucleus, and 50 per cent towards it, and likewise towards either horizontal direction. The accelerations are up to one order of magnitude stronger than local gravity, and are most simply explained by the combined effect of gas drag accelerating all aggregates upwards, and the recoil force from asymmetric outgassing, either from rotating aggregates with randomly oriented spin axes and sufficient thermal inertia to shift the temperature maximum away from an aggregate's subsolar region, or from aggregates with variable ice content. At least 10 per cent of the aggregates will escape the gravity field of the nucleus and feed the comet's debris trail, while others may fall back to the surface and contribute to the deposits covering parts of the Northern hemisphere. The rocket force plays a crucial role in pushing these aggregates back towards the surface. Our observations show the future back fall material in the process of ejection, and provide the first direct measurement of the acceleration of aggregates in the innermost coma (<2 km) of a comet, where gas drag is still significant.
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8.
  • Attree, N., et al. (författare)
  • Tensile strength of 67P/Churyumov-Gerasimenko nucleus material from overhangs
  • 2018
  • Ingår i: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 611
  • Tidskriftsartikel (refereegranskat)abstract
    • We directly measured twenty overhanging cliffs on the surface of comet 67P/Churyumov-Gerasimenko extracted from the latest shape model and estimated the minimum tensile strengths needed to support them against collapse under the comet's gravity. We find extremely low strengths of around 1 Pa or less (1 to 5 Pa, when scaled to a metre length). The presence of eroded material at the base of most overhangs, as well as the observed collapse of two features and the implied previous collapse of another, suggests that they are prone to failure and that the true material strengths are close to these lower limits (although we only consider static stresses and not dynamic stress from, for example, cometary activity). Thus, a tensile strength of a few pascals is a good approximation for the tensile strength of the 67P nucleus material, which is in agreement with previous work. We find no particular trends in overhang properties either with size over the similar to 10-100 m range studied here or location on the nucleus. There are no obvious differences, in terms of strength, height or evidence of collapse, between the populations of overhangs on the two cometary lobes, suggesting that 67P is relatively homogenous in terms of tensile strength. Low material strengths are supportive of cometary formation as a primordial rubble pile or by collisional fragmentation of a small body (tens of km).
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9.
  • Auger, A. -T, et al. (författare)
  • Geomorphology of the Imhotep region on comet 67P/Churyumov-Gerasimenko from OSIRIS observations
  • 2015
  • Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 583
  • Tidskriftsartikel (refereegranskat)abstract
    • Context. Since August 2014, the OSIRIS Narrow Angle Camera (NAC) onboard the Rosetta spacecraft has acquired high spatial resolution images of the nucleus of comet 67P/Churyumov-Gerasimenko, down to the decimeter scale. This paper focuses on the Imhotep region, located on the largest lobe of the nucleus, near the equator. Aims. We map, inventory, and describe the geomorphology of the Imhotep region. We propose and discuss some processes to explain the formation and ongoing evolution of this region. Methods. We used OSIRIS NAC images, gravitational heights and slopes, and digital terrain models to map and measure the morphologies of Imhotep. Results. The Imhotep region presents a wide variety of terrains and morphologies: smooth and rocky terrains, bright areas, linear features, roundish features, and boulders. Gravity processes such as mass wasting and collapse play a significant role in the geomorphological evolution of this region. Cometary processes initiate erosion and are responsible for the formation of degassing conduits that are revealed by elevated roundish features on the surface. We also propose a scenario for the formation and evolution of the Imhotep region; this implies the presence of large primordial voids inside the nucleus, resulting from its formation process.
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10.
  • Barucci, M. A., et al. (författare)
  • Detection of exposed H2O ice on the nucleus of comet 67P/Churyumov-Gerasimenko as observed by Rosetta OSIRIS and VIRTIS instruments
  • 2016
  • Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 595
  • Tidskriftsartikel (refereegranskat)abstract
    • Context. Since the orbital insertion of the Rosetta spacecraft, comet 67P/Churyumov-Gerasimenko (67P) has been mapped by OSIRIS camera and VIRTIS spectro-imager, producing a huge quantity of images and spectra of the comet's nucleus. Aims. The aim of this work is to search for the presence of H2O on the nucleus which, in general, appears very dark and rich in dehydrated organic material. After selecting images of the bright spots which could be good candidates to search for H2O ice, taken at high resolution by OSIRIS, we check for spectral cubes of the selected coordinates to identify these spots observed by VIRTIS. Methods. The selected OSIRIS images were processed with the OSIRIS standard pipeline and corrected for the illumination conditions for each pixel using the Lommel-Seeliger disk law. The spots with higher I/F were selected and then analysed spectrophotometrically and compared with the surrounding area. We selected 13 spots as good targets to be analysed by VIRTIS to search for the 2 mu m absorption band of water ice in the VIRTIS spectral cubes. Results. Out of the 13 selected bright spots, eight of them present positive H2O ice detection on the VIRTIS data. A spectral analysis was performed and the approximate temperature of each spot was computed. The H2O ice content was confirmed by modeling the spectra with mixing (areal and intimate) of H2O ice and dark terrain, using Hapke's radiative transfer modeling. We also present a detailed analysis of the detected spots.
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  • Resultat 1-10 av 83
  • [1]234567...9Nästa

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