Characterization of a Novel 53BP1-Dependent Mechanism that Promotes Non-Homologous End Joining of Deprotected Telomeres by Increasing Chromatin Mobility

When a double-stranded break (DSB) occurs in mammalian genomes, the local chromatin is altered through the modification of histones (notably the phosphorylation of H2AX) and the binding of DNA damage response factors (e.g. MDC1, 53BP1). Although several lines of evidence have pointed to a role for some of these factors in DSB repair through non-homologous end-joining (NHEJ), the mechanism of their contribution has not been established. To study the regulation of NHEJ, we have used as a model system dysfunctional telomeres, which are uncapped by the removal of the shelterin component, TRF2. As a consequence of TRF2 loss, deprotected chromosome ends trigger a sequence of events normally activated by the presence of DSBs. These include the instigation of ATMmediated activation of cell cycle checkpoints and the accumulation of DNA damage response factors at the telomeric chromatin. In addition, the NHEJ pathway repairs deprotected telomeres to generate chromosome end-to-end fusions. We have examined the roles of the Mre11/Rad50/NBS1 (MRN) complex, H2AX, MDC1, and 53BP1 in the NHEJ of dysfunctional telomeres. We have demonstrated that among these factors, 53BP1 is required for the fusion of telomeres, whereas the MRN complex, H2AX, and MDC1 only stimulate the efficiency of the repair process, most likely by mediating the recruitment of 53BP1 to uncapped chromosome ends. Furthermore, we have revealed the mechanism by which 53BP1 acts. We have shown that upon deprotection, telomeres become more dynamic and explore larger territories in a 53BP1-dependent manner. Faster mobility of DNA ends increases the chance that dysfunctional telomeres, which are uniformly scattered throughout the nucleus, will find one another and fuse. We have proposed that the dynamic behavior of DNA ends may be required to promote long-distance repair in general, and that it may play a role in other instances of NHEJ, such as during recombination in the immunoglobulin genes, where the DNA ends are initially at a distance. Furthermore, we have shown that the mechanism that promotes the mobility of uncapped chromosome ends requires microtubules. This finding suggests an unprecedented role for microtubules in the process of DNA repair in mammalian interphase cells. Moreover, it points to the existence of a trans-nuclear envelope bridge between damaged chromatin and cytoplasmic microtubules. Accordingly, our data indicate that mobility depends on the acetylation status of chromatin, signifying that specific chromatin modifications are involved in establishing that connection. Finally, we have preliminary evidence that the dynamic process that we have uncovered might play a role in the repair of all DNA lesions. We speculate that a microtubule-dependent chromatin mobility provides a proofreading mechanism preventing HDR between non-sister chromatids, possibly by physically pulling apart inappropriate connections. Overall, this thesis presents a novel view on how the dynamic behavior of DNA ends might be required for efficient and accurate repair of DNA lesions

Influence of detection of pretreatment cytogenetic abnormalities on first complete remission and survival in adult acute lymphoblastic leukemia

Objective: Treatment of acute lymphoblastic leukemia (ALL) in adults focuses on the initial assessment of the prognostic relevant cytogenetic features as well as a response-guided therapy based on molecular data. We examined the importance of molecular-cytogenetic abnormalities for complete remission (CR) rates and the overall survival (OS) in adult ALLs.Materials and Methods: Conventional cytogenetics and fluorescence in situ hybridization were performed on bone marrow cells from 33 newly-diagnosed ALL adults. Two karyotype categories [standard- risk group- normal karyotype, hyperdiplody and other structural aberrations, and high-risk group-t(11q23)/MLL, t(9;22)/bcr-abl, t(1;19), t(8;14), C-MYC and complex karyotype] and the biologically and clinically relevant ALL ploidy subgroups were prospectively defined.Results: Chromosomal abnormalities were found in 52% of the cases with a high rate of poor-risk translocations - t(9;22), t(8q24), t(11q23), t(1;19). The total CR rate was 67% and the median time for achievement 2.33 months. Male sex, an age below 35 years and the absence of high risk translocations might have contributed to the high CR rates. Female patients, hyperdiplody, low white blood cells (WBC), and random cytogenetic aberrations had the longest OS. OS, 3- and 5-years survival periods were significantly shorter for poor-risk than standard risk group (p=.015, p=.001 and p=.005, respectively).Conclusion: This study emphasizes the lack of influence of cytogenetic aberrations on the CR and the time to achieve CR. However, our observations show that these aberrations are an independent prognostic factor in adult ALL - they allow predicting therapy resistance and the OS time after intensetreatment

European Commission Initiative on Breast Cancer (ECIBC): Plenary 2016

The European Commission Initiative on Breast Cancer (ECIBC) Plenaries are an opportunity to inform representatives from the 28 EU Member States and 7 other countries participating in the ECIBC, as well as patients and other stakeholders, policymakers, and the scientific and health policy communities, about the aims, activities and achievements of the ECIBC. They also provide a platform for the exchange of ideas, feedback and input into the ECIBC. The 2016 ECIBC Plenary, entitled “When science and policy collaborate for health”, took place on 24-25 November in Varese, Italy. Its main focus was the implementation of both the voluntary European Quality Assurance scheme for Breast Cancer Services (European QA scheme) and the European guidelines for breast cancer screening and diagnosis (European Breast Guidelines). In this context, the first concrete results were presented, with the launch of the first four European Breast Guidelines recommendations on screening. The first day of the Plenary was dedicated to the JRC informing the audience about the various tools that ECIBC is developing. The second day instead, gave the floor to the audience, who informed the JRC of their views in terms of the challenges and opportunities related to implementing the ECIBC in the respective European countries. The event opened with welcome speeches from the European Commission’s Joint Research Centre (JRC), a moving presentation from a breast cancer survivor and reflections on how to ensure science makes its way into policy. The JRC and ECIBC working group members then brought the audience up to date with progress on the European QA scheme, the European Breast Guidelines, as well as the Guidelines Platform, the template for training on digital mammography, as well as about how ECIBC plans to monitor its impact. Participants also received in-depth explanations of the accreditation framework selected for the European QA scheme, as well as two countries’ experiences of using the ISO 15189 standard for accreditation, which is foreseen for the European QA scheme. The second day saw a focus on the individual countries represented at the Plenary. Presentations assessed how the European QA scheme could potentially fit into three different health systems (Scotland, the Netherlands, Romania), while a special breakout session gave national representatives from the 27 countries present (out of the 35 countries participating in the ECIBC) the chance to discuss implementation of the European Breast Guidelines and the European QA scheme themselves. The results, collected through questionnaires, fed into a roundtable debate on what needs to be done at European and national level to ensure ECIBC implementation. The meeting was closed by Member of the European Parliament and President of MEPs Against Cancer (MACs), Alojz Peterle. An evaluation of the event revealed that the third ECIBC Plenary met its aims to inform stakeholders: all responding participants felt that the event succeeded in providing a comprehensive overview of how the ECIBC is progressing, and what the challenges are. Discussions also provided the JRC with valuable information and feedback. The fourth ECIBC Plenary will take place once the results from piloting the European QA scheme are available.JRC.F.1-Health in Societ

Report on the call for feedback about The Scope of the European guidelines for breast cancer screening and diagnosis: European Commission Initiative on Breast Cancer

In 2015, the European Commission Initiative on Breast Cancer (ECIBC) started the development of the European guidelines for breast cancer screening and diagnosis (henceforth the European Breast Guidelines) under the auspices of the Directorate-General for Health and Food Safety (DG SANTE) and the technical and scientific coordination of the Directorate-General Joint Research Centre (JRC). To support the JRC in this task, a Guidelines Development Group (GDG), consisting of independent experts and individuals, was established. The European Breast Guidelines’ scope (The Scope) represented the first output of the development process of the European Breast Guidelines. Via a public call for feedback, stakeholders and individual citizens were invited to provide their feedback on The Scope. The call for feedback was open from 18 December 2015 to 17 January 2016 and an online questionnaire was made available on the ECIBC web hub via the EU Survey platform. The JRC received a total of 82 valid responses, from 40 individuals from 18 different countries and from 42 organisations from 20 different countries. During a meeting held in Varese (Italy) in March 2016, the GDG discussed the new version of The Scope which was prepared taking into account the results of the call for feedback. The Scope was finalised and approved by the GDG after some minor editing on 6 September 2016 and was later made publicly available together with this report.JRC.F.1-Health in Societ

European Commission Initiative on Breast Cancer: Concept document

The European Commission Initiative on Breast Cancer (ECIBC) is aimed at ensuring and harmonising breast cancer services quality across European countries. It is coordinated by Commission’s Joint Research Centre, under the supervision of the Directorate-General Health and Food Safety. This document describes the background of the initiative, its general goals and objectives, and its foreseen outcomes.JRC.F.1-Health in Societ

LincRNA-p21 Activates p21 In cis to Promote Polycomb Target Gene Expression and to Enforce the G1/S Checkpoint

The p53-regulated long noncoding RNA lincRNA-p21 has been proposed to act in trans via several mechanisms ranging from repressing genes in the p53 transcriptional network to regulating mRNA translation and protein stability. To further examine lincRNA-p21 function, we generated a conditional knockout mouse model. We find that lincRNA-p21 predominantly functions in cis to activate expression of its neighboring gene, p21. Mechanistically, we show that lincRNA-p21 acts in concert with hnRNP-K as a coactivator for p53-dependent p21 transcription. Additional phenotypes of lincRNA-p21 deficiency could be attributed to diminished p21 levels, including deregulated expression and altered chromatin state of some Polycomb target genes, a defective G1/S checkpoint, increased proliferation rates, and enhanced reprogramming efficiency. These findings indicate that lincRNA-p21 affects global gene expression and influences the p53 tumor suppressor pathway by acting in cis as a locus-restricted coactivator for p53-mediated p21 expression.National Institutes of Health (U.S.)Howard Hughes Medical InstituteLudwig Center for Molecular OncologyDamon Runyon Cancer Research Foundatio

Quality of care indicators for head and neck cancers: The experience of the European Project RARECAREnet

Background: Monitoring and improving quality of cancer care has become pivotal today. This is especially relevant for head and neck cancers since the disease is complex, it needs multi therapy, patients tend to be older, they tend to have comorbidities and limited social support. However, information on quality of care for head and neck cancers is scarce. In the context of the project "Information Network on Rare Cancers" we aimed to identify indicators of quality of care specific for the head and neck cancers management and to measure the quality of care for head and neck cancers in different EU Member States. Methods: We defined indicators of quality of care for head and neck cancers based on a multidisciplinary and expert-based consensus process at a European level. To test the proposed indicators, we performed an observational population-based retrospective study in four countries (Ireland, Italy, Netherlands, and Slovenia) in the years 2009-2011. Results: The main quality indicators identified are: availability of formalized multidisciplinary team, participation in clinical and translational research; timeliness of care, high quality of surgery and radiotherapy, and of pathological reporting. For head and neck cancers, the quality of care did not reach the optimal standards in most of the countries analyzed. A high proportion of patients was diagnosed at an advanced disease stage, showed delays in starting treatment (especially for radiotherapy), and there was only a very limited use of multi therapy. Conclusions: According to the achieved consensus, indicators of quality of care for head and neck cancers have to cover the patient journey (i.e., diagnosis and treatment). Our results, showed suboptimal quality of care across countries and call for solutions for ensuring good quality of care for head and neck cancer patients in all EU countries. One possible option might be to refer head and neck cancer patients to specialized centers or to networks including specialized centers

The European Cancer Information System: exploring linkages between indoor radon concentrations and data on cancer burden

Exposure to radon over time has significant detrimental effects on human health. Approximately 226,000 annual radon-related deaths have been reported from 66 countries (1). Many countries have a radon action plan, in order to reduce the harmful effects of radon exposure on the general public. Maps are routinely used to assist with mitigation strategies and delineate areas of priority regulation. Standard regulations in the European Union include the requirement for workplaces to test and the requirement to have reduction methods in newly built homes. Such laws are assigned systematically to areas that are understood to have high values of indoor radon. This article demonstrates that the boundaries of radon priority areas may vary, depending on the data set and methods used. We propose a table and a decision matrix to assist in choosing the most appropriate visual aid according to the purpose for which the map is to be used. We conclude that no single radon map is suitable to fit all objectives, and some maps are more suitable than others depending on the purpose

Dotting the “i” of Interoperability in FAIR Cancer-Registry Data Sets

To conform to FAIR principles, data should be findable, accessible, interoperable, and reusable. Whereas tools exist for making data findable and accessible, interoperability is not straightforward and can limit data reusability. Most interoperability-based solutions address semantic description and metadata linkage, but these alone are not sufficient for the requirements of inter-comparison of population-based cancer data, where strict adherence to data-rules is of paramount importance. Ontologies, and more importantly their formalism in description logics, can play a key role in the automation of data-harmonization processes predominantly via the formalization of the data validation rules within the data-domain model. This in turn leads to a potential quality metric allowing users or agents to determine the limitations in the interpretation and comparability of the data. An approach is described for cancer-registry data with practical examples of how the validation rules can be modeled with description logic. Conformance of data to the rules can be quantified to provide metrics for several quality dimensions. Integrating these with metrics derived for other quality dimensions using tools such as data-shape languages and data-completion tests builds up a data-quality context to serve as an additional component in the FAIR digital object to support interoperability in the wider sense

Cancer burden indicators in Europe: insights from national and regional information

With more than 3 million new cases and 1.4 million deaths estimated for 2018 , cancer represents the second most important cause of death and morbidity in the EU-28 . Population-based cancer registration represents the 'gold' standard for the provision of unbiased information on cancer burden in a defined population and how it is changing over time. Population-based cancer registries (PBCRs) collect, manage and analyse data on patients diagnosed with cancer within a defined geographical area over a certain calendar period. They are invaluable resources for the clinical and epidemiological investigation of cancer and have a unique role in supporting public health officials and agencies in the planning and evaluation of cancer prevention and control programmes. The European Network of Cancer Registries (ENCR) , in operation since 1990, was established within the framework of the Europe Against Cancer Programme of the European Commission. The ENCR promotes collaboration between cancer registries, defines data collection standards, and supports cancer registries as data providers for the supply of information necessary to quantify and monitor the burden of cancer in the European Union and Europe .JRC.F.1-Health in Societ