ALBERT

Beschreibung: Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10 –39 ; Region 3: rs2853677, P = 3.30 x 10 –36 and P Conditional = 2.36 x 10 –8 ; Region 4: rs2736098, P = 3.87 x 10 –12 and P Conditional = 5.19 x 10 –6 , Region 5: rs13172201, P = 0.041 and P Conditional = 2.04 x 10 –6 ; and Region 6: rs10069690, P = 7.49 x 10 –15 and P Conditional = 5.35 x 10 –7 ) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10 –18 and P Conditional = 7.06 x 10 –16 ). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Beschreibung: The bright gamma-ray quasar 4C +55.17 is a distant source ( z  = 0.896) with a hard spectrum at GeV energies as observed by the Large Area Telescope (LAT) on board the Fermi satellite. This source is identified as a good source candidate for very high energy (VHE; 〉30 GeV) gamma-rays. In general, VHE gamma-rays from distant sources provide a unique opportunity to study the extragalactic background light (EBL) and underlying astrophysics. The flux intensity of this source in the VHE range is investigated. Then, constraints on the EBL are derived from the attenuation of gamma-ray photons coming from the distant blazar. We searched for a gamma-ray signal from this object using the 35 h observations taken by the MAGIC (Major Atmospheric Gamma-ray Imaging Cherenkov) telescopes between 2010 November and 2011 January. No significant VHE gamma-ray signal was detected. We computed the upper limits of the integrated gamma-ray flux at the 95 per cent confidence level of 9.4 10 –12 and 2.5 10 –12  cm –2  s –1 above 100 and 200 GeV, respectively. The differential upper limits in four energy bins in the range from 80 to 500 GeV are also derived. The upper limits are consistent with the attenuation predicted by low-flux EBL models on the assumption of a simple power-law spectrum extrapolated from LAT data.

Beschreibung: The number of known very high energy (VHE) blazars is ~50, which is very small in comparison to the number of blazars detected in other frequencies. This situation is a handicap for population studies of blazars, which emit about half of their luminosity in the -ray domain. Moreover, VHE blazars, if distant, allow for the study of the environment that the high-energy -rays traverse in their path towards the Earth, like the extragalactic background light (EBL) and the intergalactic magnetic field (IGMF), and hence they have a special interest for the astrophysics community. We present the first VHE detection of 1ES 0033+595 with a statistical significance of 5.5. The VHE emission of this object is constant throughout the MAGIC observations (2009 August and October), and can be parametrized with a power law with an integral flux above 150 GeV of (7.1 ± 1.3) x 10 –12 photons cm –2 s –1 and a photon index of (3.8 ± 0.7). We model its spectral energy distribution (SED) as the result of inverse Compton scattering of synchrotron photons. For the study of the SED, we used simultaneous optical R -band data from the KVA telescope, archival X-ray data by Swift as well as INTEGRAL , and simultaneous high-energy (HE, 300 MeV–10 GeV) -ray data from the Fermi Large Area Telescope (LAT) observatory. Using the empirical approach of Prandini et al. ( 2010 ) and the Fermi LAT and MAGIC spectra for this object, we estimate the redshift of this source to be 0.34 ± 0.08 ± 0.05. This is a relevant result because this source is possibly one of the 10 most distant VHE blazars known to date, and with further (simultaneous) observations could play an important role in blazar population studies, as well as future constraints on the EBL and IGMF.

Beschreibung: Indications of a GeV component in the emission from gamma-ray bursts (GRBs) are known since the Energetic Gamma-Ray Experiment Telescope observations during the 1990s and they have been confirmed by the data of the Fermi satellite. These results have, however, shown that our understanding of GRB physics is still unsatisfactory. The new generation of Cherenkov observatories and in particular the MAGIC telescope, allow for the first time the possibility to extend the measurement of GRBs from several tens up to hundreds of GeV energy range. Both leptonic and hadronic processes have been suggested to explain the possible GeV/TeV counterpart of GRBs. Observations with ground-based telescopes of very high energy (VHE) photons ( E  〉 30 GeV) from these sources are going to play a key role in discriminating among the different proposed emission mechanisms, which are barely distinguishable at lower energies. MAGIC telescope observations of the GRB 090102 ( z  = 1.547) field and Fermi Large Area Telescope data in the same time interval are analysed to derive upper limits of the GeV/TeV emission. We compare these results to the expected emissions evaluated for different processes in the framework of a relativistic blastwave model for the afterglow. Simultaneous upper limits with Fermi and a Cherenkov telescope have been derived for this GRB observation. The results we obtained are compatible with the expected emission although the difficulties in predicting the HE and VHE emission for the afterglow of this event makes it difficult to draw firmer conclusions. Nonetheless, MAGIC sensitivity in the energy range of overlap with space-based instruments (above about 40 GeV) is about one order of magnitude better with respect to Fermi . This makes evident the constraining power of ground-based observations and shows that the MAGIC telescope has reached the required performance to make possible GRB multiwavelength studies in the VHE range.

Beschreibung: Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8 ), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03–1.07), P = 1 x 10 –5 . Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS ( P = 3 x 10 –6 ), yielding a combined OR (95% CI) of 1.06 (1.04–1.08), P = 1 x 10 –9 . Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.

Beschreibung: Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03–1.21), P = 1.4 x 10 –8 ]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.