The 100,000 genomes project
Tim Hubbard @timjph Genomics England King’s College London, King’s Health Partners Wellcome Trust Sanger Institute
Pharmacogenetics and Stratified Medicine Wellcome Trust Genome Campus 14th January 2015 Steps in UK towards E-Health Research, Genomic Medicine
• Health data to Research – 2006 Crea on of OSCHR • Increase coordina on 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 Crea on 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: h p://www.number10.gov.uk/news/uk-life-sciences-get-government-cash-boost/ BIS/DH: h p://www.dh.gov.uk/health/2011/12/nhs-adop ng-innova on/ 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: h p://www.dh.gov.uk/health/2012/01/genomics/ BIS: h p://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 pa ents 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 exis ng 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 transloca ons 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 diagnos c need with a proband from the NHS in England • Evidence of previous gene c tes ng • Prospec ve collec on but will include legacy collec ons • Family structures: ideally parent-offspring trios • Provision of Genomics England informed consent • Availability of clinical and further phenotypic data • Blood samples for DNA extrac on 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
• Diagnos c reports that are accessible and meaningful • Dynamic serial repor ng - evolving findings • Primary findings: • Known pathogenic and expected pathogenic variants on known genes • Secondary “looked for” findings (currently for 10 condi ons): • Strong cancers predisposi on and familial hypercholesterolemia • For example Lynch syndrome, BRCA1/2, mul ple endocrine neoplasia (MEN1), VHL • Carrier states of reproduc ve importance (currently for 12 condi ons): • Thalassemia, sickle cell, hemophilia A, …
• Read and variant level data accessible to NHS referring teams • Pa ents can request genomic data files from Genomics England • Pa ents are consented to be contacted up to four mes a year Genomics England Pilots • Phase 1- Sequencing and Annota on Compe on • 4 providers 15 samples (5 tumour – normal pairs and 5 germline) • Tes ng Sequencing QA and annota on
• Phase 2a-2000 Rare Inherited Disease WGS- 30x depth – over 2014 • Partnering NIHR BioResource and Transla onal Research Collabora ve • 5 centres - 928 samples since end of November- 1st 96 are in sequencing.
• Phase 2b- 3000 Cancer Pa ents (Lung, Breast, Ovary, Prostate & Colon) • Soma c (?50-80x) and germline (30-40x) – tendering now • Op mise Molecular Pathology pipeline • 11 CRUK Centres and BRCs
• Pathogens will be with Public Health England 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 Annota on
Clinical Sequence Interpretation Validation
GeL Clinical Database NHS Action Sequencing and Annota on assessment
• Sequencing bake-off – Samples sent to par cipants; returned sequence assessed – Evalua on on quality and coverage – Informed sequencing contract • Annota on bake-off – Sequence sent to par cipants (BAM+VCF) • Rare diseases: trio • Cancer: germline + tumour – Harder than assessing sequencing – Gold standard less well defined – Lack of established data standards Implementa on of Main Programme • Sequencing: contract signed with Illumina; Wellcome Trust Sequencing Centre Building at Hinxton • Annota on: 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 Interpreta on 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
h p://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 Founda on Trust; • South London NHS: Led by Guy’s and St Thomas’ NHS Founda on Trust. • North West Coast NHS GMC: Led by Liverpool Women’s NHS Founda on Trust. • Greater Manchester NHS GMC: Led by Central Manchester University Hospitals NHS Founda on Trust • University College London Partners NHS GMC: Led by Great Ormond Street Hospital NHS Founda on Trust • North East and North Cumbria NHS GMC: Led by The Newcastle upon Tyne Hospitals NHS Founda on Trust. • Oxford NHS GMC: Led by Oxford University Hospitals Founda on Trust. • South West Peninsula NHS GMC: Led by Royal Devon & Exeter NHS Founda on Trust. • Wessex NHS GMC: Led by University Hospital Southampton NHS Founda on Trust. • Imperial College Health Partners NHS GMC: Led by Imperial College Healthcare NHS Trust. • West Midlands NHS GMC: Led by University Hospitals Birmingham NHS Founda on Trust. Genomics England – Proposed data flows
Pa ent Consent Sequencing Sample Sample Centres repository Clinical Gene cs, EHR Primary Care Cancer & Hospital episodes Public Health. Refreshable iden fiable Clinical NHS Trusts, Data, linked to anonymised Pa ents & Public Whole Genome Sequence Clinical Report Pilots: Annota on Selected Centres, ‘Apps’ CRUK, BRCs
Main Program: Safe haven: Genomic Medicine Fire wall Anonymised Clinical data and Centres Pa ent data DNA sequence stays on NHS side
Only GeCIP processed results pass Clinicians & Industry outside Academics Genomics England Clinical Interpreta on Partnership - GECIP
Aims: • to op mise clinical data and sample collec on, clinical repor ng and data interpreta on for return to clinicians and pa ents • to perform research to further improve our understanding of the implica ons of the findings for genomic medicine in the clinical se ng and • to provide a rich training environment for trainees both within the Genomics Educa on Programmes of Health Educa on England. Genomics England Clinical Interpreta on Partnership - GECIP
• UK –led and self-organised into domains • Partnership with researchers, the NHS and Trainees. • Possible forma on of a precompe ve consor um 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 diagnos cs and therapies. • Recognises that to get to a therapy will require significant addi onal R&D which we aim to s mulate 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 mee ng and web cast 5th December 2014 • Work with poten al 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 pa ents • Working with NHS, academics and industry to drive Genomic Medicine into the NHS • Support that with educa on • Leave a legacy of NGS Centres, sample pipeline and biorepository, large-scale data store that makes this usable by the NHS • New diagnos cs and therapies and opportuni es for pa ents • By end of 2017 Acknowledgements
Interna onal Human Genome Project and Subsequence consor a to collect sequence of genomes and popula ons
Ensembl, GENCODE Annota on Consor um, ENCODE, Genome Reference Consor um
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