The 100,000 project

Tim Hubbard @timjph Genomics England King’s College , King’s Health Partners Sanger Institute

Pharmacogenetics and Stratified Medicine Wellcome Trust Campus 14th January 2015 Steps in UK towards E-Health Research, Genomic Medicine

• Health data to Research – 2006 Creaon of OSCHR • Increase coordinaon between funders: MRC and NIHR – 2007 OSCHR E-health board • Enable research access to UK EHR data • Build capacity for research on EHR data • Genomics to Health – 2009 House of Lords report on Genomic Medicine – 2010 Creaon of Human Genomic Strategy Group (HGSG) 2011: UK Life Sciences Strategy

Office for Life Sciences Office for Life Sciences

Strategy for UK Life Sciences

No10: hp://www.number10.gov.uk/news/uk-life-sciences-get-government-cash-boost/ BIS/DH: hp://www.dh.gov.uk/health/2011/12/nhs-adopng-innovaon/ 2012: Human Genome Strategy Group report UK Life Science Strategy Update; 100K Genomes

Industrial Strategy: government and industry in partnership

Strategy for UK Life Sciences One Year On

DH: hp://www.dh.gov.uk/health/2012/01/genomics/ BIS: hp://www.gov.uk/office-for-life-sciences/ Genomics England

http://www.genomicsengland.co.uk/ @genomicsengland Genomics England - mission

• 100,000 whole genome sequences in NHS paents with rare diseases and cancers from the NHS in England • Generate health and wealth • Legacy of infrastructure, human capacity and capability • Enable large scale genomics research

Scale compared to exisng WGS

• 1000 genomes and UK10K – low coverage genomes (~4x illumina) • Limited number of ‘clinical grade’ WGS – TCGA: ~700 – ICGC: ~700 – WGS 500: 500 Now is the moment to commit to WGS

Data Type Large-scale structural changes Balanced translocaons Distant consanguinity Uniparental disomy Novel/known coding variants Novel/known non- coding variants

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• 7 Novel genes for disease MENDELIAN • 6 Novel phenotypes for Of 95 families, to date • known genes 23 families have new clinical diagnosis • NB pre-screened for known genes

• 2 pathogenic regulatory • result will increase with follow-up variants in or downstream

of known candidate genes • 74 families in follow up studies • 6 genes missed by prior • Over 50% of these have strong lead Sanger Sequencing candidate

WTCHG, Oxford: http://www.well.ox.ac.uk/wgs500 Rare Diseases – inclusion criteria

• Rare disease with residual unmet diagnosc need with a proband from the NHS in England • Evidence of previous genec tesng • Prospecve collecon but will include legacy collecons • Family structures: ideally parent-offspring trios • Provision of Genomics England informed consent • Availability of clinical and further phenotypic data • Blood samples for DNA extracon and mul-omic samples

Cancer – inclusion criteria

• Lung, breast, colon, prostate, ovary, some leukaemias • Rare and childhood cancers, unknown primary • Provision of Genomics England informed consent • Availability of clinical and further phenotypic data • Tumour DNA primarily from FFPE samples Feedback to the NHS

• Diagnosc reports that are accessible and meaningful • Dynamic serial reporng - evolving findings • Primary findings: • Known pathogenic and expected pathogenic variants on known genes • Secondary “looked for” findings (currently for 10 condions): • Strong cancers predisposion and familial hypercholesterolemia • For example Lynch syndrome, BRCA1/2, mulple endocrine neoplasia (MEN1), VHL • Carrier states of reproducve importance (currently for 12 condions): • Thalassemia, sickle cell, hemophilia A, …

• Read and variant level data accessible to NHS referring teams • Paents can request genomic data files from Genomics England • Paents are consented to be contacted up to four mes a year Genomics England Pilots • Phase 1- Sequencing and Annotaon Compeon • 4 providers 15 samples (5 tumour – normal pairs and 5 germline) • Tesng Sequencing QA and annotaon

• Phase 2a-2000 Rare Inherited Disease WGS- 30x depth – over 2014 • Partnering NIHR BioResource and Translaonal Research Collaborave • 5 centres - 928 samples since end of November- 1st 96 are in sequencing.

• Phase 2b- 3000 Cancer Paents (Lung, Breast, Ovary, Prostate & Colon) • Somac (?50-80x) and germline (30-40x) – tendering now • Opmise Molecular Pathology pipeline • 11 CRUK Centres and BRCs

• Pathogens will be with Process Overview

Sample Sequence Variants Candidate Clinical Clinical DNA (BAM) (VCF) Variants Interpretation Action Process Overview

Sample Sequence Variants Procured DNA (BAM) (VCF) Sequence

Variants Candidate Clinical Procured (VCF) Variants Interpretation Annotaon

Clinical Sequence Interpretation Validation

GeL Clinical Database NHS Action Sequencing and Annotaon assessment

• Sequencing bake-off – Samples sent to parcipants; returned sequence assessed – Evaluaon on quality and coverage – Informed sequencing contract • Annotaon bake-off – Sequence sent to parcipants (BAM+VCF) • Rare diseases: trio • Cancer: germline + tumour – Harder than assessing sequencing – Gold standard less well defined – Lack of established data standards Implementaon of Main Programme • Sequencing: contract signed with Illumina; Wellcome Trust Sequencing Centre Building at Hinxton • Annotaon: ten groups selected for 2nd phase assessment

• Data: Award from MRC to build datacentre for GeCIP • Samples: Tender for NHS Genomic Medicine Centres • Research: Genomics England Clinical Interpretaon Partnership (GeCIP) launched

• Biorepository: to be established

Genomic Medicine Centres (GMC)

• Designated local NHS Lead and extended team • Capacity and capability networks • High fidelity phenotypes • Access to data and samples • February start date

hp://www.england.nhs.uk/wp-content/uploads/2014/10/nhs-gmcs-stg2-i-fin.pdf Eleven Genome Medicine Centres announced

• East of England NHS GMC: Led by Cambridge University Hospitals NHS Foundaon Trust; • South London NHS: Led by Guy’s and St Thomas’ NHS Foundaon Trust. • North West Coast NHS GMC: Led by Liverpool Women’s NHS Foundaon Trust. • Greater Manchester NHS GMC: Led by Central Manchester University Hospitals NHS Foundaon Trust • University College London Partners NHS GMC: Led by Great Ormond Street Hospital NHS Foundaon Trust • North East and North Cumbria NHS GMC: Led by The Newcastle upon Tyne Hospitals NHS Foundaon Trust. • Oxford NHS GMC: Led by Oxford University Hospitals Foundaon Trust. • South West Peninsula NHS GMC: Led by Royal Devon & Exeter NHS Foundaon Trust. • Wessex NHS GMC: Led by University Hospital Southampton NHS Foundaon Trust. • Imperial College Health Partners NHS GMC: Led by Imperial College Healthcare NHS Trust. • West Midlands NHS GMC: Led by University Hospitals Birmingham NHS Foundaon Trust. Genomics England – Proposed data flows

Paent Consent Sequencing Sample Sample Centres repository Clinical Genecs, EHR Primary Care Cancer & Hospital episodes Public Health. Refreshable idenfiable Clinical NHS Trusts, Data, linked to anonymised Paents & Public Whole Genome Sequence Clinical Report Pilots: Annotaon Selected Centres, ‘Apps’ CRUK, BRCs

Main Program: Safe haven: Genomic Medicine Fire wall Anonymised Clinical data and Centres Paent data DNA sequence stays on NHS side

Only GeCIP processed results pass Clinicians & Industry outside Academics Genomics England Clinical Interpretaon Partnership - GECIP

Aims: • to opmise clinical data and sample collecon, clinical reporng and data interpretaon for return to clinicians and paents • to perform research to further improve our understanding of the implicaons of the findings for genomic medicine in the clinical seng and • to provide a rich training environment for trainees both within the Genomics Educaon Programmes of Health Educaon England. Genomics England Clinical Interpretaon Partnership - GECIP

• UK –led and self-organised into domains • Partnership with researchers, the NHS and Trainees. • Possible formaon of a precompeve consorum of a limited number of industry partners. • All data generated contributes to the Genomics England Dataset and are available to all. • Designed to accelerate academic/industry partnership and development of diagnoscs and therapies. • Recognises that to get to a therapy will require significant addional R&D which we aim to smulate here in the UK. • IP owned by Genomics England but freely licensed

GeCIP Status and forward plans

• Launched Wellcome trust 27th June 2014 • Call for Expressions of Interest and Guidance • Open meeng and web cast 5th December 2014 • Work with potenal GeCIP domains • Deadline for receipt of EOIs 26th January 2015 • Early February shaping final introductory GeCIPs • Mid-late February 2015 – announce introductory GeCIPs Genomics England • 100,000 WGS of NHS paents • Working with NHS, academics and industry to drive Genomic Medicine into the NHS • Support that with educaon • Leave a legacy of NGS Centres, sample pipeline and biorepository, large-scale data store that makes this usable by the NHS • New diagnoscs and therapies and opportunies for paents • By end of 2017 Acknowledgements

Internaonal Human Genome Project and Subsequence consora to collect sequence of genomes and populaons

Ensembl, GENCODE Annotaon Consorum, ENCODE, Genome Reference Consorum

NHS England, Department of Health, Advisory groups developing plans for Genomic Medicine in UK, Genomics England

Genomics England

King’s College London, King’s Health Partners