project_met_randgrijs_2pxProject management and coordination
Lead: LUMC Leiden University Medical Center 
WP Leader: Peter Devilee

WP1 will cover the coordination of the administrative activities of the project, organize meetings and oversee the overall legal, contractual, ethical, financial and administrative management. Additional management tasks include coordination of knowledge management, controlling the quality of the performance and the achievement of milestones and deliverables, overseeing the promotion of gender equality in the project, overseeing science and societal issues related to the research activities conducted within the project and obtaining audit certificates from the participants. WP1 will also comprise risk management. This will entail identification, assessment and follow-up of threats and opportunities.

Objectives
  1. Plan and guide the administrative part of the project (following decisions made in the General Assembly), including administering and distributing the European Commission funds in a timely fashion and keeping records of such financial allocations (informing the European Commission of such allocations when requested).
  2. Coordinate BRIDGES while fulfilling all legal requirements of the European Commission.
  3. Ensure that work packages are carried out according to the timetable and advising Participants on the work that needs to be performed (in collaboration with the General Assembly).
  4. Identify potential problems at an early stage and provide timely and effective solutions.
  5. Set up quality assurance and quality control procedures where necessary (in collaboration with the General Assembly).
  6. Set up systems for and supervising the production of financial (cost statements) and scientific reports (in collaboration with the scientific coordinator) for the European Commission at stipulated intervals (the reports may be drawn up by other groups within the project).
  7. Implement a review and assessment structure to monitor BRIDGES with respect to objectives, milestones, deliverables and the Consortium Agreement.
  8. Implement the suggestions forwarded by the Scientific Advisory Board
Deliverables

Deliverable 1.1: Establishment of General Assembly, Management Office and Working Groups (M1)
Deliverable 1.2: Project Website (M6)
Deliverable 1.3: Dissemination of variants (M60)
Deliverable 1.4: Kick-off Meeting (M3)
Deliverable 1.5: Midterm Meeting (M36)
Deliverable 1.6: Final Meeting (M60)

Targeted Sequencingsequence
Lead:  CNIO – Fundacion Centro Nacional de Investigaciones Oncologocas Carlos III
WP Leader: Javier Benitez

State-of-the art DNA screening will be used to evaluate all suspected breast cancer genes in a sample of 30,000 breast cancer cases and 30,000 matched controls.

 Objectives
  1. Rare variant detection in 27 known breast cancer genes in 60,000 DNA samples (Panel 1)
  2. Rare variant detection in a further set of genes, to be determined from combined analyses of exome sequence datasets (Panel 2)
  3. Validation of the predictive value of established genes/variants from Panels 1 and 2, by sequencing the BRIDGES panel in 3,000 prospective samples
Deliverables

Deliverable 2.1: Gene selection Panel 1 (M6)
Deliverable 2.2: Sequencing results Panel 1 (M24)
Deliverable 2.3: Sensitivity of Panel 1 (M24)
Deliverable 2.4: Gene selection Panel 2 (M18)
Deliverable 2.5: Sequencing results Panel 2 (M36)
Deliverable 2.6: Sensitivity of Panel 2 (M36)
Deliverable 2.7: Gene selection BRIDGES Panel (M42)
Deliverable 2.8: Sequencing results BRIDGES Panel (M54)

Milestones

Milestone 1: Samples collected (M6)
Milestone 2: Gene selection Panel1 (M6)
Milestone 7: Panel 1 sequencing completed (M18)
Milestone 8: Gene selection Panel 2 (M18)
Milestone 15: Panel 2 sequencing completed (M30)
Milestone 24: Sequencing of BRIDGES panel completed (M54)

18794107_sData management, analysis and risk model development
Lead: UCAM – The chancellor, masters and scholars of the university of Cambridge
WP Leader : Douglas Easton

In WP3, in-silico analyses will be used to evaluate the likely pathogenicity of observed variants. Both case-control and family-based analyses will be used to estimate risks associated with different classes of genetic variants, and combine this information into a unified risk prediction model, which will build on the existing algorithm BOADICEA. This will provide individualised estimates of risk that incorporate the effects of variants in all known susceptibility genes, together with family history, SNP profile, breast density, and lifestyle risk factors.

Objectives
  1. To derive age-specific risk estimates for breast cancer associated with variants in approximately 50 BC genes and hence define a BRIDGES panel of breast cancer susceptibility genes.
  2. To derive a comprehensive breast cancer risk model, incorporating the effects of the BRIDGES panel of genes, their associations with tumour subtypes, effects of variant pathogenicity and other risk factors.
  3. To develop online tools to facilitate presentation of mutation classification, and to provide individualised breast cancer risk prediction.
Deliverables

Deliverable 3.1: Risk estimates Panel 1 (M36)
Deliverable 3.2: Combined analysis of exome and gene panel sequencing (M36)
Deliverable 3.3: Risk estimates Panel 2 (M54)
Deliverable 3.4: Report on BOADICEA-PLUS (M54)
Deliverable 3.5: Upgraded Alamut Tool (M54)
Deliverable 3.6: Risk model validation (M54)
Deliverable 3.7: Predictive value of functional analyses (M60)

Milestones

Milestone 3: HAnDEL database up and running (M12)
Milestone 4: BCAC database up and running (M12)
Milestone 10: In-silico analysis of sequence data of first gene panel completed (M24)
Milestone 16: In-silico analysis of sequence data of second gene panel completed (M36)
Milestone 21: BOADICEA-PLUS completed (M48)
Milestone 26: BOADICEA-PLUS validated in prospective setting (M60)
Milestone 27: Validated BOADICEA-PLUS disseminated via web interface (M60)
Milestone 28: Statistical analyses of cohorts 1 and 2 completed (M60)

dna_gel_kweekFunctional analysis of gene variants
Lead: LUMC – Leiden University Medical Center
WP Leader: Maaike Vreeswijk

Selected variants will be evaluated in vitro for their impact on protein function or on mRNA processing. WP3 will then evaluate whether functional-based variant classification is more strongly correlated with risk than in-silico classification, to provide the most rational basis for risk assessment.

Objectives
  1. Produce comprehensive catalogues of alternative splicing events (including tissue-specific events) at each gene in the BC-HR gene set (genes involved in Fanconi/BRCA/double-strand break repair, see 1.3.3.10 for definition).
  2. Development of large-scale in vitro minigene-based RNA splicing assays for BC-HR genes.
  3. Determine the effect on RNA splicing of genetic variants identified in WP2, and selected by WP3.
  4. Generate 3DM models to predict effect of missense changes for 27 Panel 1 genes.
  5. Development of a high-throughput in vitro assay to allow rapid testing of the effect of missense variants on BCHR protein function.
  6. Determine the effect on protein function of genetic variants in BC-HR genes identified in WP2, and selected by 3DM, using the methodology developed in (4).
  7. Exploit results from (3) and (6) to enhance bioinformatic prediction tools and risk analysis.
Deliverables

Deliverable 4.1: mCherry-cDNA constructs for 11 BCHR genes (M12)
Deliverable 4.2: A catalogue of naturally occurring alternative splicing (M24)
Deliverable 4.3: A high-throughput functional analysis system (RIgORouS) (M24)
Deliverable 4.4: VUSPlot (M24)
Deliverable 4.5: 27 3DM Models (M24)
Deliverable 4.6: A panel of validated minigene-based splicing assays (M36)
Deliverable 4.7: 250 mCherry-cDNA constructs with VUS (M48)
Deliverable 4.8: Results from RIgORouS analysis (M54)
Deliverable 4.9: A catalogue of (non-)spliceogenic variants (M54)

Milestones

Milestone 5: siRNA-based knockdown established (M12)
Milestone 11: Scanning of naturally occurring alternative splice variants completed (M24)
Milestone 12: Assessment of complementation of deficient phenotype completed (M24)
Milestone 13: RIgORouS completed (M24)
Milestone 14: VUSplot available (M24)
Milestone 17: Minigene constructs for 11 BC-HR genes available (M36)
Milestone 22: Analysis by the RIgORouS pipeline of 250 variants completed (M48)
Milestone 25: 250 spliceogenic variants analyzed by minigene assay (M54)

45916413_sClinical Implementation
Lead: UKK – Klinikum der Universitaet zu Koeln
WP Leader: Ria Schmutzler

Translate individualised risk prediction into the clinical domain. WP5 will undertake various projects to enhance standardisation of risk communication by clinicians in patient counselling sessions across the EU, and to identify subjective criteria in counselees’ risk perception and decision making, so as to harmonize clinical management. Risk estimates pre- and post-test result will be compared, thereby allowing us to assess the validity and utility of adding comprehensive genomics data to the currently available risk prediction.

Objectives
  1. Implement an objective structured risk communication strategy based on the BOADICEAPLUS risk prediction tool.
  2. Provide instruments for the identification of psychosocial distress and identify subjective criteria in counselees’ risk perception and decision making.
  3. Explore the impact of BOADICEAPLUS on risk categorization as compared to the current model, with respect to its potential public health implications.
  4. Establish and implement recommendations for the structural and procedural quality of trans-sectoral professional cooperation and communication between GPs, Cancer Centers and Familial Cancer Centers.
Deliverables

Deliverable 5.1: Survey results of BOADICEA (M24)
Deliverable 5.2: Validated instruments for the identification of patients with psychological distress (M24)
Deliverable 5.3: An e-Learning tool for genetic counsellors (M36)
Deliverable 5.4: Patient decision aid for counselees (M36)
Deliverable 5.5: A template for psychological intervention (M36)
Deliverable 5.6: Position report on best practice and recommendations for genetic counselling (M60)
Deliverable 5.7: Survey results of BOADICEA-PLUS (M60)

Milestones

Milestone 6: Questionnaires for BOADICEA surveys completed (M12)
Milestone 9: Translation of PAHC in four languages completed (M18)
Milestone 18: E-learning steps 1 to 3 completed (M36)
Milestone 19: Patient decision aid completed (M36)
Milestone 20: Accrual of Cohort 1 for prospective observational study completed (M36)
Milestone 23: Accrual of Cohort 2 for prospective observational study completed (M48)
Milestone 28: Statistical analyses of cohorts 1 and 2 completed (M60)
Milestone 29: Genetic counseling guideline completed (M60)