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A poster presented at the 36th European Immunogenetics and Histocompatibility Conference by the RDA / EOSC Future Domain Ambassador for Health Ethics. It describes the main challenges the discipline faces and describes the tools available to make data FAIR. It gives some recommendations for EFI to take onboard as Open Sciences becomes a major policy aspect.&nbsp

DFS by tumor stage stratified by genomic classifier

Supplementary Methods

Clinical information and 12 gene mutation status for cohorts C1-C3

Supplementary Tables S3-S13

Purpose:Patients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing.Experimental Design:The somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework.Results:Tumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy.Conclusions:Genomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the ∼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design.

Presentation at The 11th Edition of The International Colloquium of Social Sciences and Communication (ACUM 2022) and the National RSS Conference, Brasov, Romania, 27 - 28 October 2022

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in

On 16 July 2020, the Court of Justice of the European Union issued their decision in the Schrems II case concerning Facebook’s transfers of personal data from the EU to the US. The decision may have significant effects on the legitimate transfer of personal data for health research purposes from the EU. This article aims: (i) to outline the consequences of the Schrems II decision for the sharing of personal data for health research between the EU and third countries, particularly in the context of the COVID-19 pandemic; and, (ii) to consider certain options available to address the consequences of the decision and to facilitate international data exchange for health research moving forward.

Renal cell carcinomas (RCC) are characterized by their heterogenous clinical outcomes, and due to their indeterminate behavior and the absence of routine biomarkers, it is difficult to identify patients who are at high-risk for relapse after curative nephrectomy. To identify genomic biomarkers for clear cell RCC (ccRCC) risk-stratification we interrogated somatic mutation status of 12 RCC-relevant genes using next-generation sequencing (NGS) in tumor-normal pairs from 943 patients with matched follow up data from the Cancer Genomics of the Kidney (CAGEKID) study. We examined associations between genomically-defined patient groups, explained below, and disease-free as well as RCC-specific survival independently in two cohorts of patients (N=469 for cohort 1; 474 for cohort 2). We used the Kaplan-Meier method with log-rank tests to compare survival functions, and Cox proportional hazards models to stratify for patient stage and age to estimate association of each group with survival. RCC-specific survival was assessed with a competing-risks method to include deaths from other causes. Within these cohorts, 76.4% of patients harbored somatic mutations in VHL, the most common driver gene in ccRCC. The most commonly mutated genes within VHL-mutated tumors were PBRM1 (39.7%), SETD2 (19%), BAP1 (14.3%), and KDM5C (8.3%). Less frequently mutated genes included ATM, COL11A1, DMD, TP53, and TRRAP (~3-5%).Among VHL-driven tumors, we identified a new genomic classifier on the basis of the number of mutations in additional RCC driver genes in the panel examined. Patients were classified based on the presence of mutations only in VHL (VHL+0), those with mutations in VHL and one other driver gene (VHL+1), two other driver genes (VHL+2), and 3 or more other driver genes (VHL≥3). We observed within both cohorts that both the risk of disease recurrence as well as RCC-specific death were associated with an increased number of mutations within this classification. When stratified for patient stage and age, the hazard-ratio for 5-year disease-free survival for VHL≥3 patients was 6.69 (p=0.000212), 4.31 for VHL+2 (p=0.000862), and 2.43 for VHL+1 (p=0.035662), compared to patients with only mutations in VHL. These observations were replicated in the second patient cohort, with hazards ratios of 4.55, 2.49, and 1.40, for VHL≥3, VHL+2, and VHL+1 classified patients respectively, indicating that risk of disease recurrence increases with the number of driver mutations. Notably, tumor mutational burden (TMB) was not significantly different between the aforementioned groups, demonstrating that our classifier is independent of TMB. We created a model based on a set of 12 RCC-relevant genes, which can predict risk of relapse for the ~80% of patients with ccRCC that are VHL-driven. This classification can be defined based on a small panel of genes, making it easily applicable to the clinic, in the context of tumor or liquid biopsy analysis. Citation Format: Kate I. Glennon, Naveen S. Vasudev, Ghislaine Scelo, Michelle Wilson, Louis Letourneau, Robert Eveleigh, Nazanin Nourbehesht, Madeleine Arseneault, Antoine Paccard, Lars Egevad, Juris Viksna, Edgars Celms, Sharon M. Jackson, Behnoush Abedi-Ardekani, Anne Y. Warren, Peter J. Selby, Sebastian Trainor, Michael Kimuli, Naeem Soomro, Adebanji Adeyoju, Poulam Patel, Magdalena B. Wozniak, Ivana Holcatova, Antonin Brisuda, Vladimir Janout, Estelle Chanudet, David Zaridze, Anush Moukeria, Oxana Shangina, Lenka Foretova, Marie Navratilova, Dana Mates, Viorel Jinga, Ljiljana Bogdanovic, Bozidar Kovacevic, Anne Cambon-Thomsen, Guillaume Bourque, Alvis Brazma, Jörg Tost, Paul Brennan, Mark Lathrop, Yasser Riazalhosseini, Rosamonde E. Banks. Genomic classification to refine prognosis in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB113.

Research data are a vital component of the scientific record. Discovering and assessing data for possible reuse in future research is challenging. The Belmont Forum has recently awarded funds to th...

Despite the fact that the implementation of the FAIR principles (Findable, Accessible, Reusable, Interoperable) has become necessary in new research projects to meet the requirements of funding organisations and respond to some funders calls, many institutions do not consider data sharing through implementation of the FAIR principles as a research output, when evaluating researchers. However, this is an essential aspect to ensure reproducibility and re-usability of research and therefore, it should be highly encouraged, recognized as such, and even rewarding this kind of behavior could be considered. . In order to make data FAIR, various steps have to be defined to ensure FAIRification. The larger the community, the larger the need for a stepwise FAIRification procedure approved by the whole community. In this chain, each of the stakeholders has to fulfill its functions on long term approaches (governance, policies, data stewardship research). Several institutions define various stakeholders for FAIR data sharing within the whole disciplinary community. To improve the realisation of the FAIR principles, it is now essential to describe in a common way: i) each of the actors having a possible impact on the FAIRification of research data as well as their roles in these FAIRification processes, ii) the FAIRification landscape at the international level in which each of the stakeholders is located by identifying the resources and networks useful for the different communities and iii) each of these stakeholders (concerning not only FAIRification, but also raising awareness of FAIR, governance of data sharing, training and evaluation of practices and their recognition / encouragement). Based on the ongoing work of the SHAring Reward & Credit (SHARC) Interest Group, this poster proposes i) a description of institutional FAIR landscape, of available resources and a vision of the stakeholders,.ii) a diagram of the links and responsibilities of each actor in an iterative FAIRification process. Of course the variation in the research and data science organisation between institutions has to be taken into account when implementing FAIR principles but this approach and tentative clarification of actors is a first step that can then be adapted to each national or disciplinary context.

Next-generation sequencing techniques enable unsolicited findings to be detected. This discovery raises ethical questions concerning the return of these findings. Our study aimed to highlight the views of the general public, patients under supervision and health professionals concerning the acceptability of disclosing unsolicited results to patients. In total, 449 participants assessed scenarios, consisted of all combinations of three factors (patient’s information and consent, prevention and treatment of the unsolicited disease and doctor’s decision). The response profiles were grouped into six clusters. The participants took ethical aspects into account, but health professionals also considered the medical aspects to a greater extent.

What for? to foster data sharing by improving recognition of the work required How? by providing a set of recommendations to guide researchers and other relevant stakeholders (research institutions administrators, funders, policy makers and publishers/editors) in moving through the necessary steps towards crediting and rewarding in the data/resources-sharing process (in progress); and to encourage the adoption of data sharing activities-related criteria in the research evaluation process at the institutional, national and European/international levels. As part of it, 3 human readable assessment tools are under development that will assess semi-quantitatively the fairness knowledge & practices of scientists: 1.1 extensive FAIRness external assessment grid 52 criteria so far 1.2 simplified FAIRness external assessment grid (can be used as a quick self-assessment grid) 18 essential criteria https://zenodo.org/record/2551500#.XGK4llxKg2w 2.2 extensive checklist for fairness self-assessment (adapted from the 2 previous grids)

IF 3.636 (2017); International audience; In oncology, the expanding use of multi-gene panels to explore familial cancer predisposition and tumor genome analysis has led to increased secondary findings discoveries (SFs) and has given rise to important medical, ethical, and legal issues. The American College of Medical Genetics and Genomics published a policy statement for managing SFs for a list of genes, including 25 cancer-related genes. Currently, there are few recommendations in Europe. From June 2016 to May 2017, the French Society of Predictive and Personalized Medicine (SFMPP) established a working group of 47 experts to elaborate guidelines for managing information given on the SFs for genes related to cancers. A subgroup of ethicists, lawyers, patients’ representatives, and psychologists provided ethical reflection, information guidelines, and materials (written consent form and video). A subgroup with medical expertise, including oncologists and clinical and molecular geneticists, provided independent evaluation and classification of 60 genes. The main criteria were the “actionability” of the genes (available screening or prevention strategies), the risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into three classes: for class 1 genes (n = 36), delivering the information on SFs was recommended; for class 2 genes (n = 5), delivering the information remained questionable because of insufficient data from the literature and/or level of evidence; and for class 3 genes (n = 19), delivering the information on SFs was not recommended. These guidelines for managing SFs for cancer-predisposing genes provide new insights for clinicians and laboratories to standardize clinical practices.

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

Le terme de biobanque designe une collection d’echantillons biologiques associes a des donnees personnelles, destinee a servir la recherche scientifique. Les pratiques de recueil et de conservation du materiel biologique sont en constante evolution. Elles s’adaptent a la fois aux contextes changeants des institutions scientifiques, aux innovations d’ordre technologique et a l’emergence de nouvelles formes d’organisations. Ces adaptations doivent aussi permettre de valoriser les collections en multipliant les usages possibles des ressources biologiques et leur reutilisation future.Les orientations favorisant le developpement des biobanques sur le long terme posent cependant probleme du point de vue de l’ethique de la recherche biomedicale. Parce que nul n’est en mesure de predire pour quelle etude specifique les echantillons et donnees recueillis au sein des biobanques serviront precisement dans l’avenir, les eventuels participants des « nouvelles biobanques » se trouvent dans l’impossibilite de consentir a des recherches dont on ne peut anticiper ni la nature, ni la finalite. Les incertitudes relatives aux directions, methodes et enjeux de la recherche a venir empechent de proposer une procedure de « consentement eclaire » adaptee au present.Alors que l’anticipation constitue un enjeu technique et scientifique de taille dans la realisation des « nouvelles biobanques », nous proposons de l’envisager comme une dimension a part entiere de l’ethique appliquee aux biobanques. L’etude de pratiques scientifiques qui inscrivent les biobanques dans le temps long nous amene a penser le lien entre organisation, technologie et ethique.

Genomic technologies are developing at a time when greater public involvement in research and clinical governance is sought. To this end, empirical bioethics studies, although conceptualized as academic endeavors, may draw on the inclusion of laypeople to justify informing policy. Doing so, they face similar concerns as those addressed to public consultations which cannot be termed democratic a priori and may reinforce the authority of experts. We reflect on these concerns in the process of analyzing the results of a qualitative analysis of eight focus groups (64 participants) held in France during 2010–2012, designed to understand laypeople's views of the ethical debates surrounding genomic medicine. We examine how the notions of “lay” and “expert” play in the framework of the study and how participants situate themselves along this divide. This understanding of the social context in which the publics are situated enables a more reflexive and accurate ethical analysis.

In 2013, the American College of Medical Genetics (ACMG) examined the issue of incidental findings in whole exome and whole genome sequencing, and introduced recommendations to search for, evaluate and report medically actionable variants in a set of 56 genes. At a debate held during the 2014 European Society for Human Genetics Conference (ESHG) in Milan, Italy, the first author of that paper presented this view in a debate session that did not end with a conclusive vote from the mainly European audience for or against reporting back actionable incidental findings. In this meeting report, we elaborate on the discussions held during a special meeting hosted at the ESHG in 2013 from posing the question 'How to reach a (European) consensus on reporting incidental findings and unclassified variants in diagnostic next generation sequencing'. We ask whether an European consensus exists on the reporting of incidental findings in genome diagnostics, and present a series of key issues that require discussion at both a national and European level in order to develop recommendations for handling incidental findings and unclassified variants in line with the legal and cultural particularities of individual European member states.

The systemic challenges of the COVID-19 pandemic require cross-disciplinary collaboration in a global and timely fashion. Such collaboration needs open research practices and the sharing of research outputs, such as data and code, thereby facilitating research and research reproducibility and timely collaboration beyond borders. The Research Data Alliance COVID-19 Working Group recently published a set of recommendations and guidelines on data sharing and related best practices for COVID-19 research. These guidelines include recommendations for clinicians, researchers, policy- and decision-makers, funders, publishers, public health experts, disaster preparedness and response experts, infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations), and other potential users. These guidelines include recommendations for researchers, policymakers, funders, publishers and infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations). Several overarching themes have emerged from this document such as the need to balance the creation of data adherent to FAIR principles (findable, accessible, interoperable and reusable), with the need for quick data release; the use of trustworthy research data repositories; the use of well-annotated data with meaningful metadata; and practices of documenting methods and software. The resulting document marks an unprecedented cross-disciplinary, cross-sectoral, and cross-jurisdictional effort authored by over 160 experts from around the globe. This letter summarises key points of the Recommendations and Guidelines, highlights the relevant findings, shines a spotlight on the process, and suggests how these developments can be leveraged by the wider scientific community.

As next-generation sequencing technologies (NGS) are increasingly used in the clinic, one issue often pointed out in the literature is the fact that their implementation "blurs the line" between research and healthcare. Indeed, NGS data obtained through research study may have clinical significance, and patients may consent that their data is shared in international databases used in research. This blurred line may increase the risk of therapeutic misconception, or that of over-reporting incidental findings. The law has been used to impose a distinction between the two contexts, but this distinction may not always be as clear in the practice of clinical genomics. To illustrate this, we reviewed the legal frameworks in France and Quebec on the matter, and asked the opinion of stakeholders who use NGS to help cancer and rare disease patients in practice. We found that while there are clear legal distinctions between research and clinical care, bridges between the two contexts exist, and the law focuses on providing appropriate protections to persons, whether they are patients or research participants. The technology users we interviewed expressed that their use of NGS was designed to help patients, but harbored elements pertaining to research as well as care. We hence saw that NGS technologies are often used with a double objective, both individual care and the creation of collective knowledge. Our results highlight the importance of moving towards research-based care, where clinical information can be progressively enriched with evolutive research results. We also found that there can be a misalignment between scientific experts' views and legal norms of what constitutes research or care, which should be addressed. Our method allowed us to shed light on a grey zone at the edge between research and care, where the full benefits of NGS can be yielded. We believe that this and other evidence from the realities of clinical research practice can be used to design more stable and responsible personalized medicine policies.

Data sharing statements and promotion is a strong reality but challenging, especially when considering the many obstacles that remain on several fronts. Among these obstacles is the lack of relevant and recognized rewarding mechanisms for the very specific efforts required to share organized datasets and physical resources (Cambon-Thomsen et al., 2011; Mabile et al., 2016). The RDA-SHARC interest group is an interdisciplinary volunteer member-based group set up to unpack and improve crediting and rewarding mechanisms in the data/resources sharing process. The objectives are: 1/ To review the existing rewarding mechanisms and their limits in various scientific communities, and to identify key factors to improve the process and optimize the sharing of datasets and bioresources; i.e. data and physical samples (ex: tools, incentives, requirements...). 2/ To develop processes for stepwise adoption of principles and implementation measures tuned to national, local and institutional contexts. 3/ To rely upon this analysis to encourage the inclusion of physical bioresources sharing- related criteria in the research evaluation process at the European and national institutional levels; 4/ To disseminate information and findings to diverse communities of stakeholders

International audience; With progress in medical genetics, genome-sequencing techniques are becoming more and more efficient. However, these genetic tests may lead to the detection of unsolicited genetic findings, i.e. findings that are not the primary purpose of the screening. New ethical issues have emerged, in particular the question of whether to disclose these unsolicited findings to the patient or not. Forty-seven patients under supervision in a Medical Genetics service, 15 health professionals and 107 members of the French general population expressed their opinion regarding the appropriateness of disclosing an unsolicited high penetrance genetic finding in 36 scenarios containing three pieces of information on: a) patient information and consent;b) possibility of prevention and treatment of the detected genetic disease; and c) disclosure of the results by the physician (e.g., no disclosure of the unsolicited results). Four positions were found that were called Respect for patient’s autonomy, Beneficence to patient, Non-maleficence, and Always appropriate.; Con el progreso en medicina genética, las técnicas de secuencias de genomas están volviéndose más eficientes. Sin embargo, estos test genéticos pueden llevar a la detección de hallazgos no solicitados, e.g., hallazgos que no son el propósito primario del escaneo. Nuevos problemas éticos han surgido, en particular la pregunta de si revelar o no estos hallazgos no solicitados al paciente. 47 Pacientes bajo supervisión en un servicio de Medicina Genética, 15 profesionales de la salud y 107 miembros de la población general francesa, expresaron su opinión respecto a lo apropiado de revelar un hallazgo genético no solicitado de alto efecto en 36 escenarios con 3 piezas de información sobre: a) información del paciente y consentimiento, b) posibilidad de prevención y tratamiento de la enfermedad genética detectada, y c) revelación de los resultados por parte del médico (e.g., no revelar de los resultados no solicitados). Se encontraron cuatro posiciones que fueron llamadas Respeto por la autonomía del paciente, Beneficencia al paciente, No-maleficencia, y Siempre apropiado.

Collections intended for purely academic purposes are run on a nonprofit basis, whereas commercially managed collections are intended to make a profit for their owners by placing on the market samples private researchers can buy when they do not have their own source of research materials. In recent years, researchers using collections for multicentric projects have been reflecting on how collections can best be used. Calls for applications for European research programs stipulate that consortia conduct their research in accordance with European and international ethical guidelines.

In order to foster data sharing, the RDA-SHARC (SHAring Rewards & Credit) interest group has been set up to unpack and improve crediting and rewarding mechanisms in the data/resources sharing process. As part of the objectives, two assessment grids are being developed using criteria to establish if data are compliant to the F.A.I.R principles (findable /accessible / interoperable / reusable). The criteria used are based on the work from FORCE 11*, and on the basis of the Open Science Career Assessment Matrix designed by the EC Working group on Rewards under Open science.

International audience; Currently, a great deal of biomedical research in fields such as epidemiology, clinical trials and genetics is reliant on vast amounts of biological and phenotypic information collected and assembled in biobanks. While many resources are being invested to ensure that comprehensive and well-organised biobanks are able to provide increased access to, and sharing of biomedical samples and information, many barriers and challenges remain to such responsible and extensive sharing. Germane to the discussion herein is the barrier to collecting and sharing bioresources related to the lack of proper recognition of researchers and clinicians who developed the bioresource. Indeed, the efforts and resources invested to set up and sustain a bioresource can be enormous and such work should be easily traced and properly recognised. However, there is currently no such system that systematically and accurately traces and attributes recognition to those doing this work or the bioresource institution itself. As a beginning of a solution to the "recognition problem", the Bioresource Research Impact Factor/Framework (BRIF) initiative was proposed almost a decade and a half ago and is currently under further development. With the ultimate aim of increasing awareness and understanding of the BRIF, in this article, we contribute the following: (1) a review of the objectives and functions of the BRIF including the description of two tools that will help in the deployment of the BRIF, the CoBRA (Citation of BioResources in journal Articles) guideline, and the Open Journal of Bioresources (OJB); (2) the results of a small empirical study on stakeholder awareness of the BRIF and (3) a brief analysis of the ethical dimensions of the BRIF which allow it to be a positive contribution to responsible biobanking.

OBJECTIVE: For patients with metastatic renal cell cancer (mRCC), treatment choice is mainly based on clinical parameters. With many treatments available and the limited response to treatment and associated toxicities, there is much interest in identifying better biomarkers for personalized treatment. EuroTARGET aims to identify and characterize host- and tumor-related biomarkers for prediction of response to tyrosine kinase inhibitor therapy in mRCC. Here, we describe the EuroTARGET mRCC patient cohort. METHODS AND MATERIALS: EuroTARGET is a European collaborative project designed as an observational study for which patients with mRCC were recruited prospectively in 62 centers. In addition, 462 patients with mRCC from previous studies were included. Detailed clinical information (baseline and follow-up) from all patients was entered in web-based case record forms. Blood was collected for germline DNA and pharmacokinetic/pharmacodynamic analyses and, where available, fresh-frozen tumor material was collected to perform tumor DNA, RNA, kinome, and methylome analyses. RESULTS: In total, 1,210 patients with mRCC were included. Of these, 920 received a tyrosine kinase inhibitor as first-line targeted treatment (sunitinib [N = 713, 78%], sorafenib [N = 41, 4%], or pazopanib [N = 166, 18%]) and had at least 6 months of outcome assessment (median follow-up 15.3 months [interquartile range: 8.5-30.2 months]). Germline DNA samples were available from 824 of these patients, fresh-frozen tumor material from 142 patients, fresh-frozen normal kidney tissue from 95 patients, and tissue microarrays created from formalin-fixed paraffin-embedded tumor material from 247 patients. Of the 920 patients, germline DNA variant chip data were successfully generated for 811 patients (Illumina HumanOmniExpress BeadChip). For 80 patients, next-generation exome sequencing of germline and tumor DNA was performed, tumor RNA sequencing was performed for 124 patients, kinome activity measured and processed for 121 patients (PamChip), and methylome data (Illumina Infinium HumanMethylation450 BeadChip) were created for 116 RCC tissues (and 23 normal kidney tissues). For 73 out of the 920 patients, all platform data types were generated. In addition, 40 patients were included in a pharmacokinetic/pharmacodynamic phase IV substudy. CONCLUSIONS: Analysis of EuroTARGET cohort data will contribute to personalization of therapy for patients with mRCC. The extensive clinical data and multiplatform EuroTARGET data will be freely available. We would like to thank all patients who participated and their treating physicians for inviting them. Sí

Resume Objectifs Determiner l’impact des polymorphismes nucleotidiques simples (SNP) dans les genes IL-2RA (rs2104286) et IL-2RB (rs743777 et rs3218253) sur les risques d’erosion chez les patients atteints de polyarthrite rhumatoide (PR). Methodes Ce travail derive de deux cohortes prospectives de PR precoce : les cohortes ESPOIR (n = 439) et RMP (n = 180). Les proportions de patients avec erosion au depart et a un an en fonction des genotypes de l’IL-2RA (rs2104286) ou des haplotypes generes par les deux SNP de l’IL-2RB ont ete comparees dans la population totale et chez les patients positifs pour les ACPA. Une meta-analyse determinant le risque erosif en fonction des haplotypes des deux SNP de l’IL-2RB a ete realisee en utilisant la methode de Mantel-Haenszel. Un modele multivarie a ete utilise afin de determiner l’effet independant des haplotypes d’IL-2RB sur le risque erosif. Resultats L’haplotype AC d’IL-2RB etait associe de maniere significative avec les taux d’erosion chez les patients positifs pour les ACPA dans la cohorte ESPOIR (taux d’erosion : AC/AC : 78 % contre GC ou GT/GC ou GT : 44 %, p = 0,001). Une meta-analyse des cohortes ESPOIR et RMP a confirme que le fait de porter l’haplotype AC etait significativement associe au taux d’erosion a un an dans la population totale (OR [IC95 %] = 1,92 [1,14–3,22], p = 0,01) et chez les patients ACPA-positifs (OR [IC95 %] = 3,34 [1,68–6,67], p = 0,0006). Un modele multivarie dans la cohorte ESPOIR a demontre l’effet independant de l’haplotype AC (6,03 [1,94–18,69], p = 0,002) sur le risque erosif chez les patients ACPA-positifs. Conclusion Un haplotype forme par deux SNP localises dans le gene IL-2RB etait associe a l’etat erosif dans la PR precoce.

Online availability of direct-to-consumer health genetic testing services for various diseases and behavioural traits appears to have created a business dynamic since its beginning around the turn of the millennium. What are the marketing strategies implemented by the companies commercialising these tests and the social expectations they feed on? From a quantitative and qualitative analysis of the websites offering such tests for health, it appears that these companies have based their expansion on a triple-branch market: 'healthism', contemporary claims revolving around the individuation of 'biopolitics', and biosocial bonding. Each of these three marketing strategies raises a number of socio-ethical issues that require careful consideration in the face of an unprecedented surge of the genetic testing market.

With the human genome project running from 1989 until its completion in 2003, and the incredible advances in sequencing technology and in bioinformatics during the last decade, there has been a shift towards an increase focus on studying common complex disorders which develop due to the interplay of many different genes as well as environmental factors. Although some susceptibility genes have been identified in some populations for disorders such as cancer, diabetes and cardiovascular diseases, the integration of this information into the health care system has proven to be much more problematic than for single gene disorders. Furthermore, with the 1000$ genome supposedly just around the corner, and whole genome sequencing gradually being integrated into research protocols as well as in the clinical context, there is a strong push for the uptake of additional genomic testing. Indeed, the advent of public health genomics, wherein genomics would be integrated in all aspects of health care and public health, should be taken seriously. Although laudable, these advances also bring with them a slew of ethical and social issues that challenge the normative frameworks used in clinical genetics until now. With this in mind, we highlight herein 5 principles that are used as a primer to discuss the ethical introduction of genome-based information and genome-based technologies into public health.

Background Communicating results to research participants is an issue frequently discussed in terms of ethics. It has specific features when involving large-scale paediatric cohorts. High-throughput biological explorations reveal also incidental findings of medical relevance. This work analyses existing frameworks for managing such issues and proposes a policy grounded in the experience acquired in the FP7 EU project MeDALL – Mechanisms of the Development of ALLergy. Methods A bibliographical analysis was performed using law, ethics and academic documentation. Empirical data were acquired through informed consent forms from 9 of the 13 cohorts used in MeDALL and from replies to a general questionnaire (n = 10) on ethical issues sent to consortium members. Group discussions and expert consultations were conducted during project meetings. Results The notions of research results and incidental findings remain ambiguous as no agreed definition exists. The most appropriate terms are communication of results and disclosure of incidental findings. No legal norm and no specific guidance govern these issues in paediatric research at European level. Relevant policies depend on decisions in each cohort or project. The policy proposed states that these issues should be discussed during the informed consent process, with due attention to involvement of children, and a balance of interests between children, parents and society. A moral duty for researchers to communicate such information only applies if certain medical and social criteria are met. Conclusions As there is no consensus within European Birth cohorts how to deal with results and incidental findings, we propose a general policy.

In recent years, the cost of generating genome information has shown a rapid decline.1, 2 High-throughput genomic technologies make it possible to sequence the whole exome or genome of a person at a price that is affordable for some health-care systems. More services based on these technologies are now becoming available for patients, raising the issue of how to ensure that these are provided appropriately. In order to determine both the clinical utility of genetic testing and assure a high quality of the analysis, the interpretation and communication of the results must be discussed so that patients can receive appropriate advice and genetic testing. The Public and Professional Policy Committee (PPPC) and the Quality Committee of the European Society of Human Genetics (ESHG) addressed these challenges at a joint workshop in Gothenburg, Sweden, in 2010.3 PPPC also organised workshops in Amsterdam, the Netherlands (January 2011 in collaboration with the EU-funded project TECHGENE, January 2012). A report for the Health Council of the Netherlands served as a background document for the PPPC's reflections.4 Focusing on the clinical diagnostics setting, this paper is intended to contribute to the discussion and the development of guidelines in this fast-moving field, and provide recommendations for health-care professionals. The paper and recommendations were posted on the ESHG website from 20 June to 1 August 2012 for comment by the membership. The final version was approved by the ESHG Board in December 2012.

Next-generation sequencing is radically changing how DNA diagnostic laboratories operate. What started as a single-gene profession is now developing into gene panel sequencing and whole exome and genome sequencing (WES/WGS) analyses. With further advances in sequencing technology and concomitant price reductions, whole genome sequencing (WGS) will soon become the standard and be routinely offered. Here we focus on the critical steps involved in performing WGS, with a particular emphasis on points where WGS differs from WES, the important variables that should be taken into account, and the quality control measures that can be taken to monitor the process. The points discussed here, combined with recent publications on guidelines for reporting variants, will facilitate the routine implementation of WGS into a diagnostic setting. This article is protected by copyright. All rights reserved. ispartof: Human Mutation vol:38 issue:8 pages:912-921 ispartof: location:United States status: published

Objectives The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in the pathogenesis of bone erosions in rheumatoid arthritis (RA). The aim of this study was to test the association between 11 single-nucleotide polymorphisms (SNPs) located on RANK, RANKL and OPG genes and anticitrullinated peptide antibody (ACPA) presence or erosions in RA. Methods Patients: This work was performed on three independent samples of French patients with RA: the Etude de Suivi des PolyArthrites Indifferenciees Recentes (ESPOIR) (n=632), Rangueil Midi-Pyrenees (RMP) (n=249) and French Rheumatoid Arthritis Genetic Consortium (FRAGC) (n=590) cohorts. Genotyping: the genotyping of 11 SNPs located on RANK , RANKL and OPG were performed by PCR. Statistical analyses: The association between the genotypes with ACPA or erosions was first tested in the ESPOIR cohort using a χ 2 test and, in the case of significant association, replicated in the RMP and FRACG cohorts. A meta-analysis on the three cohorts was performed using the Mantel-Haenszel method. Results One SNP on RANK (rs8086340) and three SNPs on RANKL (rs7984870, rs7325635, rs1054016) were significantly associated with ACPA presence, while one SNP on OPG (rs2073618) and one SNP on RANKL (rs7325635) were significantly associated with erosions in the ESPOIR cohort. Following meta-analysis performed on the three samples, the SNP on RANK and the GGG haplotype of the three SNPs located on RANKL were both significantly associated with ACPA presence, while only the SNP on OPG remained significantly associated with erosions. Conclusions This study identified one SNP located on RANK , one haplotype on RANKL associated with ACPA presence, and one SNP located on OPG associated with erosions in three different samples of French patients with RA.

More than 1,000 Web-based locus-specific variation databases (LSDBs) are listed on the Website of the Human Genetic Variation Society (HGVS). These individual efforts, which often relate phenotype to genotype, are a valuable source of information for clinicians, patients, and their families, as well as for basic research. The initiators of the Human Variome Project recently recognized that having access to some of the immense resources of unpublished information already present in diagnostic laboratories would provide critical data to help manage genetic disorders. However, there are significant ethical issues involved in sharing these data worldwide. An international working group presents second-generation guidelines addressing ethical issues relating to the curation of human LSDBs that provide information via a Web-based interface. It is intended that these should help current and future curators and may also inform the future decisions of ethics committees and legislators. These guidelines have been reviewed by the Ethics Committee of the Human Genome Organization (HUGO). Hum Mutat 31: 1179-1184, 2010. (C) 2010Wiley-Liss, Inc.

The aim of this Ethical Governance Framework is to enable any future project members of BBMRI-ERIC to operate within agreed terms with respect to participant consent, ethics committee approvals and national regulations, ensuring researchers supply and access data whilst working under a common ethical framework. The draft framework presented below has been written on the basis of other EU funded projects works in order to ensure reliability and consistency of the systems in place, with the concern that very different samples and datasets can be utilised in an ethically­-coherent manner to maximise research benefit, while acknowledging the responsibilities and obligations that are owed to research participants., ADOPT BBMRI-ERIC Deliverable D5.7

International audience; We examined the extent to which lay people and health professionals are able to assess occurrence risks for multifactorial diseases. We asked 341 participants to assess the risk of developing lung cancer, coronary artery disease or rheumatoid arthritis in 16 scenarios, each featuring a combination of four factors (family history, daily alcohol intake, daily tobacco consumption and genetic test results). Participants considered all factors. However, they accorded more weight to tobacco and genetic test results. Moreover, it appears that where one of the factors (e.g. the presence of the incriminated gene) exerted a strong influence, the influence of the other factor(s) was correspondingly weaker. The health risk judgements of health professionals were more dependent on the specific disease and were also influenced to a greater degree by genetic information than lay people.

International audience

The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues.