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| 4. |
- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 5. |
- Jiang, X., et al.
(författare)
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Shared heritability and functional enrichment across six solid cancers
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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| 14. |
- Bogdanova, Svetlana, et al.
(författare)
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The 1.80-1.74-Ga gabbro-anorthosite-rapakivi Korosten Pluton in the Ukrainian Shield: a 3-D geophysical reconstruction of deep structure
- 2004
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Ingår i: Tectonophysics. - : Elsevier BV. - 0040-1951. ; 381:1-4, s. 5-27
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Tidskriftsartikel (refereegranskat)abstract
- The deep structure of the gabbro-anorthosite-rapakivi granite ("AMCG-type") Korosten Pluton (KP) in the northwestern Ukrainian Shield was studied by 3-D modelling of the gravity and magnetic fields together with previous seismic data. The KP occupies an area of ca. 12,500 km(2) and comprises several layered gabbro-anorthositic intrusions enveloped by large volumes of rapakivi-type granitoids. Between 1.80 and 1.74 Ga, the emplacement of mafic and associated granitoid melts took place in several pulses. The 3-D geophysical reconstruction included: (a) modelling of the density distribution in the crust using the observed Bouguer anomaly field constrained by seismic data on Moho depth, and (b) modelling of the magnetic anomaly field in order to outline rock domains of various magnetisation, size and shape in the upper and lower crust. The density modelling was referred to three depth levels of 0 to 5, 5 to 18, and 18 kin to Moho, respectively. The 3-D reconstruction demonstrates close links between the subsurface geology of the KP and the structure of the lower crust. The existence of a non-magnetic body with anomalously high seismic velocity and density is documented. Most plausibly, it represents a gabbroic stock (a parent magma chamber) with a vertical extent of ca. 20 km, penetrating the entire lower crust. This stock has a half-cylindrical shape and a diameter of ca. 90 kin. It appears to be connected with a crust-mantle transitional lens previously discovered by EUROBRIDGE seismic profiling. The position of the stock relative to the subsurface outlines of the KP is somewhat asymmetric. This may be due to a connection between the magmatism and sets of opposite-dipping faults initially developed during late Palaeoproterozoic collisional deformation in the Sarmatian crustal segment. Continuing movements and disturbances of the upper mantle and the lower crust during post-collisional tectonic events between 1.80 and 1.74 Ga may account for the long-lived, recurrent AMCG magmatism.
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| 16. |
- Ferreira, MA, et al.
(författare)
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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1741-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
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| 23. |
- Dareng, EO, et al.
(författare)
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Polygenic risk modeling for prediction of epithelial ovarian cancer risk
- 2022
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 30:3, s. 349-362
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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| 31. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 32. |
- Liu, JJ, et al.
(författare)
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Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 9688-
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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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| 33. |
- Liu, JJ, et al.
(författare)
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rs2735383, located at a microRNA binding site in the 3'UTR of NBS1, is not associated with breast cancer risk
- 2016
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 36874-
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Tidskriftsartikel (refereegranskat)abstract
- NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3′-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936–1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r2 > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969–1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905–1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility.
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| 37. |
- Akiba, K., et al.
(författare)
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The LHCb VELO Upgrade module construction
- 2024
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Ingår i: Journal of Instrumentation. - : Institute of Physics Publishing (IOPP). - 1748-0221. ; 19:6
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Tidskriftsartikel (refereegranskat)abstract
- The LHCb detector has undergone a major upgrade for LHC Run 3. This Upgrade I detector facilitates operation at higher luminosity and utilises full-detector information at the LHC collision rate, critically including the use of vertex information. A new vertex locator system, the VELO Upgrade, has been constructed. The core element of the new VELO are the double-sided pixelated hybrid silicon detector modules which operate in vacuum close to the LHC beam in a high radiation environment. The construction and quality assurance tests of these modules are described in this paper. The modules incorporate 200 mu m thick, n -on -p silicon sensors bump-bonded to 130 nm technology ASICs. These are attached with high precision to a silicon microchannel substrate that uses evaporative CO 2 cooling. The ASICs are controlled and read out with flexible printed circuits that are glued to the substrate and wire -bonded to the chips. The mechanical support of the module is given by a carbon fibre plate, two carbon fibre rods and an aluminium plate. The sensor attachment was achieved with an average precision of 21 mu m, more than 99.5% of all pixels are fully functional, and a thermal figure of merit of 3 Kcm 2 W - 1 was achieved. The production of the modules was successfully completed in 2021, with the final assembly and installation completed in time for data taking in 2022.
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| 38. |
- Bogdanova, Svetlana, et al.
(författare)
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Late Palaeoproterozoic mafic dyking in the Ukrainian Shield of Volgo-Sarmatia caused by rotation during the assembly of supercontinent Columbia (Nuna)
- 2013
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Ingår i: Lithos. - : Elsevier BV. - 0024-4937. ; 174, s. 196-216
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Tidskriftsartikel (refereegranskat)abstract
- The Ukrainian Shield comprises the exposed crust of the large Palaeoproterozoic protocraton Volgo-Sarmatia, which together with the Fennoscandian crustal segment constitutes the East European Craton ("Baltica"). Geological and geophysical data indicate that 1.80 to 1.75 Ga mafic dykes related to anorthosite-mangerite-charnockite-granite (AMCG) plutons are widespread within the Ukrainian Shield. We examined their ages, distribution patterns, orientations and compositions in three different crustal blocks (Volyn, Ingul and Azov), and found close spatial relationships with major strike-slip fault systems developed during two phases of extension. The early, 1.80-1.77 Ga, generation of mafic dykes mostly follows NW (330 +/- 20 degrees) and more rarely N-S- or E-W-trending faults corresponding to major NE-SW extension (the Submoshorino phase). These dykes contain olivine dolerites, picrites, camptonites, lamprophyres, kimberlites and other rocks belonging to tholeiitic and subalkaline jotunitic series. The compositions of these dykes differ between the host blocks, but all feature upper mantle geochemical signatures such as high contents of Ni and Cr, and positive values of epsilon Nd-(1800) up to + 2.8. High degrees of REE fractionation indicate deep levels of mantle melting, which is particularly characteristic of the Ingul block as marked by the most extensive and dense mafic dyke swarms. The later, 1.76-1.75 Ga, dyke swarms occur close to the most voluminous AMCG suites of similar age and were emplaced during the second (Korsun) phase of faulting when all the older strike-slip fault zones were reactivated and partly transformed to tensional faults by E-W extension. These dyke swarms mainly trend 030 +/- 20 degrees. They are jotunitic and their isotopic signatures indicate a greater participation of crustal sources in the parent melts. The overall transtensional tectonic setting of the mafic dyking associated with the AMCG magmatism in Volgo-Sarmatia was created by convergent tectonics and postcollisional collapse of the thickened lithosphere, as well as by mantle delamination coupled with the rotation of Volgo-Sarmatia between 1.80 and 1.75 Ga. This agrees with palaeomagnetic reconstruction suggesting rotation(s) of Volgo-Sarmatia during its protracted oblique docking with Fennoscandian terranes and Laurentia as supercontinent Columbia (Nuna) was assembled. (C) 2012 Elsevier B.V. All rights reserved.
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| 40. |
- Couch, Fergus J., et al.
(författare)
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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
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| 49. |
- Kostin, Alexander I., et al.
(författare)
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Impact of pathogen reduction methods on immunological properties of the COVID-19 convalescent plasma
- 2021
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Ingår i: Vox Sanguinis. - : Wiley. - 0042-9007 .- 1423-0410. ; 116:6, s. 665-672
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Tidskriftsartikel (refereegranskat)abstract
- Background and objectives: COVID-19 convalescent plasma is an experimental treatment against SARS-CoV-2. The aim of this study is to assess the impact of different pathogen reduction methods on the levels and virus neutralizing activity of the specific antibodies against SARS-CoV2 in convalescent plasma. Materials and methods: A total of 140 plasma doses collected by plasmapheresis from COVID-19 convalescent donors were subjected to pathogen reduction by three methods: methylene blue (M)/visible light, riboflavin (R)/UVB and amotosalen (A)/UVA. To conduct a paired comparison, individual plasma doses were divided into 2 samples that were subjected to one of these methods. The titres of SARS-CoV2 neutralizing antibodies (NtAbs) and levels of specific immunoglobulins to RBD, S- and N-proteins of SARS-CoV-2 were measured before and after pathogen reduction. Results: The methods reduced NtAbs titres differently: among units with the initial titre 80 or above, 81% of units remained unchanged and 19% decreased by one step after methylene blue; 60% were unchanged and 40% decreased by one step after amotosalen; after riboflavin 43% were unchanged and 50% (7%, respectively) had a one-step (two-step, respectively) decrease. Paired two-sample comparisons (M vs. A, M vs. R and A vs. R) revealed that the largest statistically significant decrease in quantity and activity of the specific antibodies resulted from the riboflavin treatment. Conclusion: Pathogen reduction with methylene blue or with amotosalen provides the greater likelihood of preserving the immunological properties of the COVID-19 convalescent plasma compared to riboflavin.
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