Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

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.NovartisEli Lilly and CompanyAstraZenecaAbbViePfizer UKCelgeneEisaiGenentechMerck Sharp and DohmeRocheCancer Research UKGovernment of CanadaArray BioPharmaGenome CanadaNational Institutes of HealthEuropean CommissionMinistère de l'Économie, de l’Innovation et des Exportations du QuébecSeventh Framework ProgrammeCanadian Institutes of Health Researc

Genome-wide association study of germline variants and breast cancer-specific mortality

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10

Sismicité, couplages sismique-asismiques et processus transitoires de déformation dans un système de failles actives : le rift de Corinthe, Grèce

The western part of the Corinth Rift in Greece is opening at about 15 mm per year, generating one of the highest deformation rates in the world, some destructive earthquakes of magnitude M>6 per decade, and high microseismic activity irregular in space and time. In order to better understand the mechanisms related to this crustal deformation and to specify the major active structures, this research work makes use of the seismological database of the Corinth Rift Laboratory from 2000 to 2015 by finely analyzing microearthquakes and their spatio-temporal evolution. The global relocation of the seismic sources and their classification into multiplets enable to refine the geometry of the faults and to identify different mechanical behaviors. The western zone, in the middle of the gulf, is affected by fluctuations of fluid pore pressures in a geological layer, resulting in microseismic swarm migrations at a velocity of about 50 m per day. The deep multiplets of the central part, near the northern coast, are persistent and appear to be triggered by episodes of slow aseismic slip along an immature detachment, which can reach the ductile crust. The low percentage of dynamic triggering by passing seismic waves suggests that the overall state of the fault system is not at the critical breaking point. The magnitude of earthquakes is correlated with the initial impulsiveness of the rupture. These results specify the dynamics of the rift deformation, the seismic-aseismic interactions, and will make possible the improvement of the seismic hazard models of the regionLa partie ouest du rift de Corinthe, en Grèce, s'ouvre à une vitesse d'environ 15 mm par an générant un taux de déformation parmi les plus élevés au monde, quelques séismes destructeurs de magnitude M>6 par décennie, et une forte activité microsismique irrégulière spatialement et temporellement. Afin de mieux comprendre les mécanismes liés à cette déformation crustale et de préciser les structures majeures actives, ce travail de recherche exploite la base de données sismologiques du Corinth Rift Laboratory de 2000 à 2015 en analysant finement les microséismes et leur évolution spatio-temporelle. La relocalisation globale des sources sismiques ainsi que leur classification en multiplets ont permis de préciser la géométrie des failles et d'identifier des comportements mécaniques différents. La zone ouest, au milieu du golfe, est affectée par des variations de pressions de fluides dans une couche géologique, entraînant des migrations des essaims de microséismes à des vitesses d'environ 50 m par jour. Les multiplets profonds de la partie centrale, près de la côte nord, sont persistants et semblent déclenchés par des épisodes de glissements lents asismiques sur un détachement immature pouvant atteindre la croûte ductile. Le faible pourcentage de déclenchement dynamique par les ondes sismiques suggère que l'état global du système de failles n'est pas au seuil critique de rupture. La magnitude des séismes est corrélée à l'impulsivité initiale de la rupture. Ces résultats précisent la dynamique de déformation du rift, les interactions sismique-asismiques, et permettront d'améliorer les modèles d'aléas sismiques de la régio

Seismicity, seismic-aseismic couplings and transient deformation processes in an active fault system : the Corinth rift, Greece

La partie ouest du rift de Corinthe, en Grèce, s'ouvre à une vitesse d'environ 15 mm par an générant un taux de déformation parmi les plus élevés au monde, quelques séismes destructeurs de magnitude M>6 par décennie, et une forte activité microsismique irrégulière spatialement et temporellement. Afin de mieux comprendre les mécanismes liés à cette déformation crustale et de préciser les structures majeures actives, ce travail de recherche exploite la base de données sismologiques du Corinth Rift Laboratory de 2000 à 2015 en analysant finement les microséismes et leur évolution spatio-temporelle. La relocalisation globale des sources sismiques ainsi que leur classification en multiplets ont permis de préciser la géométrie des failles et d'identifier des comportements mécaniques différents. La zone ouest, au milieu du golfe, est affectée par des variations de pressions de fluides dans une couche géologique, entraînant des migrations des essaims de microséismes à des vitesses d'environ 50 m par jour. Les multiplets profonds de la partie centrale, près de la côte nord, sont persistants et semblent déclenchés par des épisodes de glissements lents asismiques sur un détachement immature pouvant atteindre la croûte ductile. Le faible pourcentage de déclenchement dynamique par les ondes sismiques suggère que l'état global du système de failles n'est pas au seuil critique de rupture. La magnitude des séismes est corrélée à l'impulsivité initiale de la rupture. Ces résultats précisent la dynamique de déformation du rift, les interactions sismique-asismiques, et permettront d'améliorer les modèles d'aléas sismiques de la régionThe western part of the Corinth Rift in Greece is opening at about 15 mm per year, generating one of the highest deformation rates in the world, some destructive earthquakes of magnitude M>6 per decade, and high microseismic activity irregular in space and time. In order to better understand the mechanisms related to this crustal deformation and to specify the major active structures, this research work makes use of the seismological database of the Corinth Rift Laboratory from 2000 to 2015 by finely analyzing microearthquakes and their spatio-temporal evolution. The global relocation of the seismic sources and their classification into multiplets enable to refine the geometry of the faults and to identify different mechanical behaviors. The western zone, in the middle of the gulf, is affected by fluctuations of fluid pore pressures in a geological layer, resulting in microseismic swarm migrations at a velocity of about 50 m per day. The deep multiplets of the central part, near the northern coast, are persistent and appear to be triggered by episodes of slow aseismic slip along an immature detachment, which can reach the ductile crust. The low percentage of dynamic triggering by passing seismic waves suggests that the overall state of the fault system is not at the critical breaking point. The magnitude of earthquakes is correlated with the initial impulsiveness of the rupture. These results specify the dynamics of the rift deformation, the seismic-aseismic interactions, and will make possible the improvement of the seismic hazard models of the regio

Update on the seismogenic potential of the Upper Rhine Graben southern region

International audienceAbstract. The Upper Rhine Graben (URG), located in France and Germany, is bordered by north–south-trending faults, some of which are considered active, posing a potential threat to the dense population and infrastructures on the Alsace plain. The largest historical earthquake in the region was the M6.5±0.5 Basel earthquake in 1356. Current seismicity (M>2.5 since 1960) is mostly diffuse and located within the graben. We build upon previous seismic hazard studies of the URG by exploring uncertainties in greater detail and revisiting a number of assumptions. We first take into account the limited evidence of neotectonic activity and then explore tectonic scenarios that have not been taken into account previously, exploring uncertainties for Mmax, its recurrence time, the b value, and the moment released aseismically or through aftershocks. Uncertainties in faults' moment deficit rates, on the observed seismic events' magnitude–frequency distribution and on the moment–area scaling law of earthquakes, are also explored. Assuming a purely dip-slip normal faulting mechanism associated with a simplified model with three main faults, Mmax maximum probability is estimated at Mw 6.1. Considering this scenario, there would be a 99 % probability that Mmax is less than 7.3. In contrast, with a strike-slip assumption associated with a four-main-fault model, consistent with recent paleoseismological studies and the present-day stress field, Mmax is estimated at Mw 6.8. Based on this scenario, there would be a 99 % probability that Mmax is less than 7.6

Both mainshock-aftershocks and swarm sequences are driven by fluid processes (Ubaye Region, French Western Alps)

International audienc

Both mainshock-aftershocks and swarm sequences are driven by fluid processes (Ubaye Region, French Western Alps)

International audienc

Both mainshock-aftershocks and swarm sequences are driven by fluid processes (Ubaye Region, French Western Alps)

International audienc