BRCA1 and BRCA2 mutations in a population-based study of male breast cancer

Background: The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear. Methods: We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk. Results: Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives. Conclusion: These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found

Things change: Women’s and men’s marital disruption dynamics in Italy during a time of social transformations, 1970-2003

We study women’s and men’s marital disruption in Italy between 1970 and 2003. By applying an event-history analysis to the 2003 Italian variant of the Generations and Gender Survey we found that the spread of marital disruption started among middle-highly educated women. Then in recent years it appears that less educated women have also been able to dissolve their unhappy unions. Overall we can see the beginning of a reversed educational gradient from positive to negative. In contrast the trend in men’s marital disruption risk appears as a change over time common to all educational groups, although with persisting educational differentials.determinants, educational differences, event history analysis, gender difference, Italy, marital disruption

Principles for the post-GWAS functional characterisation of risk loci

Several challenges lie ahead in assigning functionality to susceptibility SNPs. For example, most effect sizes are small relative to effects seen in monogenic diseases, with per allele odds ratios usually ranging from 1.15 to 1.3. It is unclear whether current molecular biology methods have enough resolution to differentiate such small effects. Our objective here is therefore to provide a set of recommendations to optimize the allocation of effort and resources in order maximize the chances of elucidating the functional contribution of specific loci to the disease phenotype. It has been estimated that 88% of currently identified disease-associated SNP are intronic or intergenic. Thus, in this paper we will focus our attention on the analysis of non-coding variants and outline a hierarchical approach for post-GWAS functional studies

Calibration and Commissioning Studies for the Mu3e Experiment

The Mu3e experiment will search for the charged lepton flavour violating decay µ + → e + e + e − . This interaction while possible in the Standard Model is suppressed to experimentally unobservable levels with a branching ratio below 10−50, hence any observation would be a clear indicator of physics beyond the Standard Model. The experiment will be based in the muon beam line, πE5, at the Paul Scherrer Institute, which can currently achieve rates of up to 108 muons per second. In this first phase of the experiment, a single event sensitivity of 2×10−15 is targeted, improving by several orders of magnitude on the current sensitivity set by the SINDRUM-I experiment. Taking into account the experimental difficulties of a high muon beam rate with low momenta decay positrons and electrons, the detector will be comprised of multiple ultra-thin tracking layers based on novel high voltage monolithic active pixel sensors providing excellent momentum and vertex resolutions. A good time resolution is also critical for the suppression of accidental backgrounds, hence a timing system combining scintillating fibres and tiles will provide precise timing information. The major focus of this thesis is on preparation for Phase I of the experiment. This includes studies of the timing system, in particular developing new methods for improving the timing performance in the track reconstruction with the scintillating fibres, and the development of a relative timing calibration method. Also presented is a study of a prototype pixel detector which gathered data with the aim to reconstruct cosmic muons. Finally, a method for extracting momentum resolutions and the feasibility of Mott scattering as a calibration tool for the detector are explored in simulation