Correlated fragile site expression allows the identification of candidate fragile genes involved in immunity and associated with carcinogenesis

Background: Common fragile sites (cfs) are specific regions in the human genome that are particularly prone to genomic instability under conditions of replicative stress. Several investigations support the view that common fragile sites play a role in carcinogenesis. We discuss a genome-wide approach based on graph theory and Gene Ontology vocabulary for the functional characterization of common fragile sites and for the identification of genes that contribute to tumour cell biology. Results: Common fragile sites were assembled in a network based on a simple measure of correlation among common fragile site patterns of expression. By applying robust measurements to capture in quantitative terms the non triviality of the network, we identified several topological features clearly indicating departure from the Erdos-Renyi random graph model. The most important outcome was the presence of an unexpected large connected component far below the percolation threshold. Most of the best characterized common fragile sites belonged to this connected component. By filtering this connected component with Gene Ontology, statistically significant shared functional features were detected. Common fragile sites were found to be enriched for genes associated to the immune response and to mechanisms involved in tumour progression such as extracellular space remodeling and angiogenesis. Moreover we showed how the internal organization of the graph in communities and even in very simple subgraphs can be a starting point for the identification of new factors of instability at common fragile sites. Conclusion: We developed a computational method addressing the fundamental issue of studying the functional content of common fragile sites. Our analysis integrated two different approaches. First, data on common fragile site expression were analyzed in a complex networks framework. Second, outcomes of the network statistical description served as sources for the functional annotation of genes at common fragile sites by means of the Gene Ontology vocabulary. Our results support the hypothesis that fragile sites serve a function; we propose that fragility is linked to a coordinated regulation of fragile genes expression

Overdiagnosis in breast cancer screening: the importance of length of observation period and lead time

PMCID: PMC3706885This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Correlated fragile site expression allows the identification of candidate fragile genes involved in immunity and associated with carcinogenesis

Common fragile sites (cfs) are specific regions in the human genome that are particularly prone to genomic instability under conditions of replicative stress. Several investigations support the view that common fragile sites play a role in carcinogenesis. We discuss a genome-wide approach based on graph theory and Gene Ontology vocabulary for the functional characterization of common fragile sites and for the identification of genes that contribute to tumour cell biology. CFS were assembled in a network based on a simple measure of correlation among common fragile site patterns of expression. By applying robust measurements to capture in quantitative terms the non triviality of the network, we identified several topological features clearly indicating departure from the Erdos-Renyi random graph model. The most important outcome was the presence of an unexpected large connected component far below the percolation threshold. Most of the best characterized common fragile sites belonged to this connected component. By filtering this connected component with Gene Ontology, statistically significant shared functional features were detected. Common fragile sites were found to be enriched for genes associated to the immune response and to mechanisms involved in tumour progression such as extracellular space remodeling and angiogenesis. Our results support the hypothesis that fragile sites serve a function; we propose that fragility is linked to a coordinated regulation of fragile genes expression.Comment: 18 pages, accepted for publication in BMC Bioinformatic

Global Mapping of DNA Conformational Flexibility on Saccharomyces cerevisiae

In this study we provide the first comprehensive map of DNA conformational flexibility in Saccharomyces cerevisiae complete genome. Flexibility plays a key role in DNA supercoiling and DNA/protein binding, regulating DNA transcription, replication or repair. Specific interest in flexibility analysis concerns its relationship with human genome instability. Enrichment in flexible sequences has been detected in unstable regions of human genome defined fragile sites, where genes map and carry frequent deletions and rearrangements in cancer. Flexible sequences have been suggested to be the determinants of fragile gene proneness to breakage; however, their actual role and properties remain elusive. Our in silico analysis carried out genome-wide via the StabFlex algorithm, shows the conserved presence of highly flexible regions in budding yeast genome as well as in genomes of other Saccharomyces sensu stricto species. Flexibile peaks in S. cerevisiae identify 175 ORFs mapping on their 3’UTR, a region affecting mRNA translation, localization and stability. (TA)n repeats of different extension shape the central structure of peaks and co-localize with polyadenylation efficiency element (EE) signals. ORFs with flexible peaks share common features. Transcripts are characterized by decreased half-life: this is considered peculiar of genes involved in regulatory systems with high turnover; consistently, their function affects biological processes such as cell cycle regulation or stress response. Our findings support the functional importance of flexibility peaks, suggesting that the flexible sequence may be derived by an expansion of canonical TAYRTA polyadenylation efficiency element. The flexible (TA)n repeat amplification could be the outcome of an evolutionary neofunctionalization leading to a differential 3’-end processing and expression regulation in genes with peculiar function. Our study provides a new support to the functional role of flexibility in genomes and a strategy for its characterization inside human fragile sites

A multi-element psychosocial intervention for early psychosis (GET UP PIANO TRIAL) conducted in a catchment area of 10 million inhabitants: study protocol for a pragmatic cluster randomized controlled trial

Multi-element interventions for first-episode psychosis (FEP) are promising, but have mostly been conducted in non-epidemiologically representative samples, thereby raising the risk of underestimating the complexities involved in treating FEP in 'real-world' services

The benefits and harms of breast cancer screening:an independent review

Whether breast cancer screening does more harm than good has been debated extensively. The main questions are how large the benefit of screening is in terms of reduced breast cancer mortality and how substantial the harm is in terms of overdiagnosis, which is defined as cancers detected at screening that would not have otherwise become clinically apparent in the woman's lifetime. An independent Panel was convened to reach conclusions about the benefits and harms of breast screening on the basis of a review of published work and oral and written evidence presented by experts in the subject. To provide estimates of the level of benefits and harms, the Panel relied mainly on findings from randomised trials of breast cancer screening that compared women invited to screening with controls not invited, but also reviewed evidence from observational studies. The Panel focused on the UK setting, where women aged 50-70 years are invited to screening every 3 years. In this Review, we provide a summary of the full report on the Panel's findings and conclusions. In a meta-analysis of 11 randomised trials, the relative risk of breast cancer mortality for women invited to screening compared with controls was 0·80 (95% CI 0·73-0·89), which is a relative risk reduction of 20%. The Panel considered the internal biases in the trials and whether these trials, which were done a long time ago, were still relevant; they concluded that 20% was still a reasonable estimate of the relative risk reduction. The more reliable and recent observational studies generally produced larger estimates of benefit, but these studies might be biased. The best estimates of overdiagnosis are from three trials in which women in the control group were not invited to be screened at the end of the active trial period. In a meta-analysis, estimates of the excess incidence were 11% (95% CI 9-12) when expressed as a proportion of cancers diagnosed in the invited group in the long term, and 19% (15-23) when expressed as a proportion of the cancers diagnosed during the active screening period. Results from observational studies support the occurrence of overdiagnosis, but estimates of its magnitude are unreliable. The Panel concludes that screening reduces breast cancer mortality but that some overdiagnosis occurs. Since the estimates provided are from studies with many limitations and whose relevance to present-day screening programmes can be questioned, they have substantial uncertainty and should be regarded only as an approximate guide. If these figures are used directly, for every 10,000 UK women aged 50 years invited to screening for the next 20 years, 43 deaths from breast cancer would be prevented and 129 cases of breast cancer, invasive and non-invasive, would be overdiagnosed; that is one breast cancer death prevented for about every three overdiagnosed cases identified and treated. Of the roughly 307,000 women aged 50-52 years who are invited to begin screening every year, just over 1% would have an overdiagnosed cancer in the next 20 years. Evidence from a focus group organised by Cancer Research UK and attended by some members of the Panel showed that many women feel that accepting the offer of breast screening is worthwhile, which agrees with the results of previous similar studies. Information should be made available in a transparent and objective way to women invited to screening so that they can make informed decisions