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- Mavaddat, Nasim, et al.
(författare)
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Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:5, s. 036-036
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Tidskriftsartikel (refereegranskat)abstract
- Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
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- Boschini, M. J., et al.
(författare)
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Solution of Heliospheric Propagation : Unveiling the Local Interstellar Spectra of Cosmic-ray Species
- 2017
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 840:2
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Tidskriftsartikel (refereegranskat)abstract
- Local interstellar spectra (LIS) for protons, helium, and antiprotons are built using the most recent experimental results combined with state-of-the-art models for propagation in the Galaxy and heliosphere. Two propagation packages, GALPROP and HelMod, are combined to provide a single framework that is run to reproduce direct measurements of cosmic-ray (CR) species at different modulation levels and at both polarities of the solar magnetic field. To do so in a self-consistent way, an iterative procedure was developed, where the GALPROP LIS output is fed into HelMod, providing modulated spectra for specific time periods of selected experiments to compare with the data; the HelMod parameter optimization is performed at this stage and looped back to adjust the LIS using the new GALPROP run. The parameters were tuned with the maximum likelihood procedure using an extensive data set of proton spectra from 1997 to 2015. The proposed LIS accommodate both the low-energy interstellar CR spectra measured by Voyager 1 and the high-energy observations by BESS, Pamela, AMS-01, and AMS-02 made from the balloons and near-Earth payloads; it also accounts for Ulysses counting rate features measured out of the ecliptic plane. The found solution is in a good agreement with proton, helium, and antiproton data by AMS-02, BESS, and PAMELA in the whole energy range.
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- Boschini, M. J., et al.
(författare)
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Deciphering the Local Interstellar Spectra of Primary Cosmic-Ray Species with HELMOD
- 2018
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 858:1
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Tidskriftsartikel (refereegranskat)abstract
- Local interstellar spectra (LIS) of primary cosmic ray (CR) nuclei, such as helium, oxygen, and mostly primary carbon are derived for the rigidity range from 10 MV to similar to 200 TV using the most recent experimental results combined with the state-of-the-art models for CR propagation in the Galaxy and in the heliosphere. Two propagation packages, GALPROP and HELMOD, are combined into a single framework that is used to reproduce direct measurements of CR species at different modulation levels, and at both polarities of the solar magnetic field. The developed iterative maximum-likelihood method uses GALPROP-predicted LIS as input to HELMOD, which provides the modulated spectra for specific time periods of the selected experiments for model-data comparison. The interstellar and heliospheric propagation parameters derived in this study are consistent with our prior analyses using the same methodology for propagation of CR protons, helium, antiprotons, and electrons. The resulting LIS accommodate a variety of measurements made in the local interstellar space (Voyager 1) and deep inside the heliosphere at low (ACE/CRIS, HEAO-3) and high energies (PAMELA, AMS-02).
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| 8. |
- Boschini, M. J., et al.
(författare)
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HelMod in the Works : From Direct Observations to the Local Interstellar Spectrum of Cosmic-Ray Electrons
- 2018
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 854:2
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Tidskriftsartikel (refereegranskat)abstract
- The local interstellar spectrum (LIS) of cosmic-ray (CR) electrons for the energy range 1 MeV to 1 TeV is derived using the most recent experimental results combined with the state-of-the-art models for CR propagation in the Galaxy and in the heliosphere. Two propagation packages, GALPROP and HELMOD, are combined to provide a single framework that is run to reproduce direct measurements of CR species at different modulation levels, and at both polarities of the solar magnetic field. An iterative maximum-likelihood method is developed that uses GALPROP-predicted LIS as input to HELMOD, which provides the modulated spectra for specific time periods of the selected experiments for model-data comparison. The optimized HelMod parameters are then used to adjust GALPROP parameters to predict a refined LIS with the procedure repeated subject to a convergence criterion. The parameter optimization uses an extensive data set of proton spectra from 1997 to 2015. The proposed CR electron LIS accommodates both the low-energy interstellar spectra measured by Voyager 1 as well as the high-energy observations by PAMELA and AMS-02 that are made deep in the heliosphere; it also accounts for Ulysses counting rate features measured out of the ecliptic plane. The interstellar and heliospheric propagation parameters derived in this study agree well with our earlier results for CR protons, helium nuclei, and anti-protons propagation and LIS obtained in the same framework.
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- Kuchenbaecker, Karoline B., et al.
(författare)
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Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers
- 2017
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 109:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 × 10-53). InBRCA2 carriers, the strongest association with BC risk was seen for the overall BCPRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 × 10-20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
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- Peterlongo, Paolo, et al.
(författare)
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FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor.
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:18, s. 5345-5355
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Tidskriftsartikel (refereegranskat)abstract
- Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.
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