Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Extent of Baseline Prostate Atrophy Is Associated With Lower Incidence of Low- and High-grade Prostate Cancer on Repeat Biopsy

Objective: To evaluate whether baseline prostate atrophy (PA) extent is associated with prostate cancer (PCa) incidence at 2-year repeat prostate biopsy in a clinical trial with systematic biopsies. Materials and Methods: We performed a retrospective analysis of 3165 men 50-75 years old with prostate-specific antigen between 2.5 and 10 ng/mL and a prior negative biopsy in the placebo arm of the Reduction by Dutasteride of PCa Events trial who underwent a 2-year repeat biopsy. PA extent was defined as the percentage of cores with atrophic changes. The association of baseline PA with positive 2-year biopsies was evaluated with logistic regression in uni- and multivariable analysis, controlling for baseline covariates. Results: PA involving none, 1%-25%, 26%-50%, 51%-75%, and >75% of the baseline cores was observed in 966 of 3165 (30.5%), 1189 of 3165 (37.6%), 677 of 3165 (21.4%), 209 of 3165(6.6%), and 124 of 3165 (3.9%) cases, respectively. More extensive PA was associated with older age, lower prostate-specific antigen, larger prostate volume, and higher prevalence of acute and chronic inflammations (all P 75% core involvement had an odds ratio for PCa of 0.65 (95% confidence interval [CI] = 0.52-0.81), 0.60 (95% CI = 0.46-0.78), 0.56 (95% CI = 0.37-0.86), and 0.35 (95% CI = 0.19-0.67), respectively. In multivariable analysis, the extent of PA was independently associated with lower PCa risk (P < .001). More extensive PA was associated with lower incidence of low-grade (Gleason 2-6) and high-grade (Gleason 7-10) PCa. Conclusion: The extent of baseline PA is independently associated with lower PCa risk in a dose-dependent fashion

Областная газета. 2006. № 113

In this article we investigate how social media-based crowdsourcing systems can be used to reengineer the innovation culture in an organization. Based on a case study of a large engineering consultancy\u27s use of a social media crowdsourcing system we investigate the impact on the organizations innovation culture using theory on organizational culture and crowdsourcing. The analysis shows that the organizational crowdsourcing event has supported an innovation culture change in the case company towards a more open approach to innovation; creating a new and different awareness of innovation, allowing for internal process innovations, empowering the employees, supporting knowledge work and collaboration across the organization to a new extent and overcoming the traditional hierarchy in the organization