Breast cancer affects more than 360,000 women per year in the EU and causes more than 90,000 deaths. Identification of women at high risk of the disease can lead to disease prevention through intensive screening, chemoprevention or prophylactic surgery. Breast cancer risk is determined by a combination of genetic and lifestyle risk factors. The advent of next generation sequencing has opened up the opportunity for testing in many disease genes, and diagnostic gene panel testing is being introduced in many EU countries. However, the cancer risks associated with most variants in most genes are unknown. This leads to a major problem in appropriate counselling and management of women undergoing panel testing. In this project, we aim to build a knowledge base that will allow identification of women at high-risk of breast cancer, in particular through comprehensive evaluation of DNA variants in known and suspected breast cancer genes. We will exploit the huge resources established through the Breast Cancer Association Consortium (BCAC) and ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles). We will expand the existing datasets by sequencing all known breast cancer susceptibility genes in 20,000 breast cancer cases and 20,000 controls from population-based studies, and 10,000 cases from multiple case families. Sequence data will be integrated with in-silico and functional data, with data on other known risk factors, to generate a comprehensive risk model that can provide personalised risk estimates. We will develop online tools to aid the interpretation of gene variants and provide risk estimates in a user-friendly format, to help genetic counsellors and patients worldwide to make informed clinical decisions. We will evaluate the acceptability and utility of comprehensive gene panel testing in the clinical genetics context.

RELENT is multidisciplinary group of scientists and clinical investigators whose goal is to develop individualized treatment for chronic autoimmune diseases, such as rheumatoid arthritis and vasculitis, that cause considerable mortality and morbidity, both from uncontrolled disease and treatment associated co-morbidities, like infection and malignancy. This requires the need to stratify patients by their outcome and to tailor immunosuppression based on much deeper knowledge of the mechanisms that control initiation and persistence of the pathogenic immune responses. The RELENT Consortium has been formed to generate this knowledge with the ultimate goal of developing treatments tailored to the specific needs of individual patients. RELENT combines the resources of seven leading European Investigators and two from US and Australia whose expertise is not available elsewhere in the world but necessary for the ambitious work program. Three SMEs will supply specific reagents and translate the results to biomarker development. This will enable RELENT to deliver its four specific research aims, namely to: i) Combine subset analysis of genome wide association studies with classical cell biology to uncover pathways that influence and ii) use multiplexed antigen arrays, whole proteome analysis and rapid mass analysis to identify protein signatures that predict outcome and response to treatment in chronic autoimmune disease. iii) Characterise T and B cell abnormalities that predispose to autoimmunity and infection by studying the ageing immune system in health and disease. iv) Analyse pathogenic effector T cells and their control by macrophages and dendritic cells and the molecules they secrete using in vivo models. We anticipate to identify common mechanisms responsible for the persistence and outcomes in severe autoimmune and inflammatory diseases in females and males and that the results should be rapidly translatable into clinical practice for the benefit of patients.