No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 16 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defense (W81XWH-10-1- 0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Project established by the National Cancer Institute and National Human Genome Research Institute.This is the author accepted manuscript. The final version is available from BMJ Group at http://dx.doi.org/10.1136/jmedgenet-2015-103529

Observation of a sudden cessation of a very-high-energy gamma-ray flare in PKS 1510-089 with H.E.S.S. and MAGIC in May 2016

The flat spectrum radio quasar (FSRQ) PKS 1510-089 is known for its complex multiwavelength behavior, and is one of only a few FSRQs detected at very high energy (VHE, E >100 GeV) -rays. VHE -ray observations with H.E.S.S. and MAGIC during late May and early June 2016 resulted in the detection of an unprecedented flare, which reveals for the first time VHE -ray intranight variability in this source. While a common variability timescale of 1.5 hr is found, there is a significant deviation near the end of the flare with a timescale of ∼ 20 min marking the cessation of the event. The peak flux is nearly two orders of magnitude above the low-level emission. For the first time, curvature is detected in the VHE -ray spectrum of PKS 1510-089, which is fully explained through absorption by the extragalactic background light. Optical R-band observations with ATOM reveal a counterpart of the -ray flare, even though the detailed flux evolution differs from the VHE lightcurve. Interestingly, a steep flux decrease is observed at the same time as the cessation of the VHE flare. In the high energy (HE, E >100 MeV) -ray band only a moderate flux increase is observed with Fermi-LAT, while the HE -ray spectrum significantly hardens up to a photon index of 1.6. A search for broad-line region (BLR) absorption features in the -ray spectrum indicates that the emission region is located outside of the BLR. Radio VLBI observations reveal a fast moving knot interacting with a standing jet feature around the time of the flare. As the standing feature is located ∼ 50 pc from the black hole, the emission region of the flare may have been located at a significant distance from the black hole. If this correlation is indeed true, VHE rays have been produced far down the jet where turbulent plasma crosses a standing shock.Accepted manuscrip

Modelling of highly extended Gamma-ray emission around the Geminga Pulsar as detected with H.E.S.S

International audienceGeminga is an enigmatic radio-quiet gamma-ray pulsar located at a mere 250 pc distance from Earth. Extended very-high-energy gamma-ray emission around the pulsar has been detected by multiple water Cherenkov detector based instruments. However, the detection of extended TeV gamma-ray emission around the Geminga pulsar has proven challenging for IACTs due to the angular scale exceeding the typical field-of-view. By detailed studies of background estimation techniques and characterising systematic effects, a detection of highly extended TeV gamma-ray emission could be confirmed by the H.E.S.S. IACT array. Building on the previously announced detection, in this contribution we further characterise the emission and apply an electron diffusion model to the combined gamma-ray data from the H.E.S.S. and HAWC experiments, as well as X-ray data from XMM-Newton

Modelling of highly extended Gamma-ray emission around the Geminga Pulsar as detected with H.E.S.S

International audienceGeminga is an enigmatic radio-quiet gamma-ray pulsar located at a mere 250 pc distance from Earth. Extended very-high-energy gamma-ray emission around the pulsar has been detected by multiple water Cherenkov detector based instruments. However, the detection of extended TeV gamma-ray emission around the Geminga pulsar has proven challenging for IACTs due to the angular scale exceeding the typical field-of-view. By detailed studies of background estimation techniques and characterising systematic effects, a detection of highly extended TeV gamma-ray emission could be confirmed by the H.E.S.S. IACT array. Building on the previously announced detection, in this contribution we further characterise the emission and apply an electron diffusion model to the combined gamma-ray data from the H.E.S.S. and HAWC experiments, as well as X-ray data from XMM-Newton

Detection of extended TeV emission around the Geminga pulsar with H.E.S.S

International audienceHighly extended gamma-ray emission around the Geminga pulsar was discovered by Milagro and verified by HAWC. Despite many observations with Imaging Atmospheric Cherenkov Telescopes (IACTs), detection of gamma-ray emission on angular scales exceeding the IACT field-of-view has proven challenging. Recent developments in analysis techniques have enabled the detection of significant emission around Geminga in archival data with H.E.S.S.. In 2019, further data on the Geminga region were obtained with an adapted observation strategy. Following the announcement of the detection of significant TeV emission around Geminga in archival data, in this contribution we present the detection in an independent dataset. New analysis results will be presented, and emphasis given to the technical challenges involved in observations of highly extended gamma-ray emission with IACTs

Observations of the Pulsar Wind Nebula HESS J1825–137 with H.E.S.S. II

International audienceWe present a new and deep analysis of the pulsar wind nebula (PWN) HESS J1825-137 with a comprehensive data set of almost 400 hours taken with the H.E.S.S. array between 2004 and 2016. The large amount of data, and the inclusion of low-threshold H.E.S.S. II data allows us to include a wide energy range of more than 2.5 orders of magnitude, ranging from 150 GeV up to 70 TeV. We exploit this rich dataset to study the morphology and the spectral distributions of various subregions of this largely extended source in more detail. We find that HESS J1825-137 is not only the brightest source in that region above 32 TeV, but is also one of the most luminous of all firmly identified pulsar wind nebulae in the Milky Way

Energy dependent morphology of the pulsar wind nebula HESS J1825-137 with Fermi-LAT

International audienceAims. Taking advantage of more than 11 years of Fermi-LAT data, we perform a new and deep analysis of the pulsar wind nebula (PWN) HESS J1825-137. Combining this analysis with recent H.E.S.S. results we investigate and constrain the particle transport mechanisms at work inside the source as well as the system evolution.Methods. The PWN is studied using 11.6 years of Fermi-LAT data between 1 GeV and 1 TeV. In particular, we present the results of the spectral analysis and the first energy-resolved morphological study of the PWN HESS J1825-137 at GeV energies, which provide new insights into the γ-ray characteristics of the nebula.Results. An optimised analysis of the source returns an extended emission region larger than 2°, corresponding to an intrinsic size of about 150 pc, making HESS J1825-137 the most extended γ-ray PWN currently known. The nebula presents a strong energy dependent morphology within the GeV range, moving from a radius of ∼1.4° below 10 GeV to a radius of ∼0.8° above 100 GeV, with a shift in the centroid location.Conclusions. Thanks to the large extension and peculiar energy-dependent morphology, it is possible to constrain the particle transport mechanisms inside the PWN HESS J1825-137. Using the variation of the source extension and position, as well as the constraints on the particle transport mechanisms, we present a scheme for the possible evolution of the system. Finally, we provide an estimate of the electron energy density and we discuss its nature in the PWN and TeV halo-like scenario.Key words: astroparticle physics / pulsars: individual: HESS J1825-137 / pulsars: individual: PSR B1823-13 / gamma rays: stars / acceleration of particle

Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility

We recently reported that a sequence variant in the cell-cycle-checkpoint kinase CHEK2 (CHEK2 1100delC) is a low-penetrance breast cancer-susceptibility allele in noncarriers of BRCA1 or BRCA2 mutations. To investigate whether other CHEK2 variants confer susceptibility to breast cancer, we screened the full CHEK2 coding sequence i

The exceptionally powerful TeV γ-ray emitters in the Large Magellanic Cloud

The Large Magellanic Cloud, a satellite galaxy of the Milky Way, has been observed with the High Energy Stereoscopic System (H.E.S.S.) above an energy of 100 billion electron volts for a deep exposure of 210 hours. Three sources of different types were detected: the pulsar wind nebula of the most energetic pulsar known, N 157B; the radio-loud supernova remnant N 132D; and the largest nonthermal x-ray shell, the superbubble 30 Dor C. The unique object SN 1987A is, unexpectedly, not detected, which constrains the theoretical framework of particle acceleration in very young supernova remnants. These detections reveal the most energetic tip of a γ-ray source population in an external galaxy and provide via 30 Dor C the unambiguous detection of γ-ray emission from a superbubble

H.E.S.S. first public test data release

The High Energy Stereoscopic System (H.E.S.S.) is an array of ground-based imaging atmospheric Cherenkov telescopes in Namibia. For the first time, the H.E.S.S. collaboration is releasing a small dataset of event lists and instrument response information. This is a test data release, with the motivation to support the ongoing efforts to define open high-level data models and associated formats, as well as open-source science tools for gamma-ray astronomy. The data are in FITS format. Open-source science tools that support this format exist already. The release data consists of 27.9 hours in total of observations of the Crab nebula, PKS 2155-304, MSH 15-52 and RX J1713.7-3946 taken with the H.E.S.S. 1 array. Most data are from 2004, the PKS 2155-304 data are from 2006 and 2008. In addition, 20.7 hours of off observations of empty fields of view are included. The targets and observations were chosen to be suitable for common analysis use cases, including point-like and extended sources for spectral and morphology measurements, as well as a variable source (PKS 2155-304) and the off dataset for background studies. The total size of the files in this data release is 42.8 MB. This is a very small subset of the thousands of hours of H.E.S.S. 1 observations taken since 2004. The quality of this dataset, and measurements derived from this data, does not reflect the state of the art for H.E.S.S. publications, e.g. the event reconstruction and gamma-hadron separation method used here is a very basic one