Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

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

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

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

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

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 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

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

Caractérisation de la diffusion bistatique du champ électromagnétique par un environnement urbain (modèle et applications)

Dans cette thèse, nous proposons un modèle 3D, nommé MESUA (Model for Electromagnetic Scattering of Urban Areas), dédié à la caractérisation du champ diffusé par une zone urbaine qui se compose d'un groupe de bâtiments pour des configurations radars, monostatique ou bistatique. Ce modèle est basé sur la technique du lancer de rayons combinée à une méthode asymptotique, la Théorie Uniforme de la Diffraction (TUD). Il est utile non seulement de connaître les mécanismes de la propagation des rayons à travers la zone observée, mais aussi d'évaluer l'amplitude et la phase du champ lointain diffracté par ce scénario au-dessus du sol. Après avoir validé notre modèle avec des résultats numériques obtenus par des codes commerciaux et des mesures, nous l'appliquons pour calculer et évaluer le champ diffracté par une zone urbaine en fonction des paramètres de celle-ci (la forme des bâtiments, la densité des bâtiments placés autour de la zone observée, ). Les résultats peuvent être utilisés afin d'évaluer la possibilité de détecter une cible localisée dans la zone urbainePARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

A user-centered and group-based approach for social data filtering and sharing

International audienceSocial networking sites (SNSs) like Facebook, Google+, Twitter, LinkedIn have become a very important part of our daily life. People are connected to multiple SNSs for networking, communicating, collaborating, sharing and seeking for information. Although, the diversity of current SNSs increases and enriches our online experience, they cause some problems. One of the major issues is that users are often overwhelmed by the huge number of social data. It is even worse as these social data are scattered across disconnected SNSs. To address such problems, we propose a user-centered and group-based approach for social data filtering and sharing. First, it allows users to aggregate their social data from different SNSs and to extract relevant contents. Users explicitly define their interests via specific queries, using information filtering techniques, the system will retrieve new corresponding contents. Second, it is expected to extend its first user-centered purpose by allowing group-based information sharing and management. Users can share some part of their own social data with and collectively define the information organization within their respective groups. To describe further and illustrate our proposed approach, a system architecture and a prototype are also presented in this paper. A primary test was carried out and showed encouraging results confirming the added values of our approach

Social Networks: Leveraging User Social Data to Empower Collective Intelligence

International audienceOnline social networks such as Facebook, Twitter or LinkedIn have become extremely popular and ubiquitous. However, users are facing problems such as the disconnected nature of social Websites, user privacy issues and the huge amount of information available for browsing. Consequently, a considerable part of interesting information remains ignored by the users. This chapter presents a possible answer to this problem based on a new approach consisting of aggregating relevant information from social networks to empower the collective intelligence shared by a given group of users. The solution is built on a user-centered approach, the main benefit of which is that each user can delegate to the system the tasks of aggregating his/her scattered social data and extracting information relevant to the topics of interest of the group. Moreover, the user is provided with helpful features to make the best decisions for choosing the information he/she is ready to share

Isotropic octupolar second harmonic generation response in LaBGeO5 glass-ceramic with spherulitic precipitation

A spherulitic crystallization of the crystalline phase LaBGeO5 is generated in the 25La2O3-25B2O3-50 GeO2 glass system. Linear and nonlinear optical properties of lanthanum borogermanate glass-ceramic have been investigated at both macroscopic and microscopic scales. Polarized μ-Raman analysis has evidenced a radial distribution of the crystallites along the c-axis inside spherulites, whereas polarized μ-Second Harmonic Generation (SHG) analysis revealed intensity maxima perpendicularly to the c-axis crystallites orientation. Polarized SHG mapping of a spherulite indicate that no dipolar response along the c-axis oriented crystallites occurs despite the individual dipolar symmetry C3 of the crystallites. At a larger mm scale, the isotropic scattering of spherulites recorded from macroscopic SHG experiment in the forward direction is consistent with an average coherent octupolar response per spherulite. These SHG analyses at different scale are both in accordance with radial antiferroelectric orientation along the c-axis of crystallites inside each spherulite