the100,000genomesproject$ open... · 2015. 10. 19. · the100,000genomesproject$ tim hubbard...
TRANSCRIPT
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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
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Steps in UK towards E-‐Health Research, Genomic Medicine
• Health data to Research – 2006 CreaEon of OSCHR
• Increase coordinaEon 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 CreaEon of Human Genomic Strategy Group (HGSG)
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2011: UK Life Sciences Strategy
Office forLife Sciences
Office forLife Sciences
Strategy for UKLife Sciences
No10: hTp://www.number10.gov.uk/news/uk-‐life-‐sciences-‐get-‐government-‐cash-‐boost/ BIS/DH: hTp://www.dh.gov.uk/health/2011/12/nhs-‐adopEng-‐innovaEon/
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2012: Human Genome Strategy Group report UK Life Science Strategy Update; 100K Genomes
Strategy for UK Life SciencesOne Year On
Industrial Strategy: government and industry in partnership
DH: hTp://www.dh.gov.uk/health/2012/01/genomics/ BIS: hTp://www.gov.uk/office-‐for-‐life-‐sciences/
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Genomics England
http://www.genomicsengland.co.uk/ @genomicsengland
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Genomics England -‐ mission
• 100,000 whole genome sequences in NHS paEents 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
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Scale compared to exisEng WGS
• 1000 genomes and UK10K – low coverage genomes (~4x illumina)
• Limited number of ‘clinical grade’ WGS – TCGA: ~700 – ICGC: ~700 – WGS 500: 500
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Now is the moment to commit to WGS
Data Type Large-‐scale
structural changes
Balanced
translo
caEo
ns
Distant
consanguinity
Uniparental
disomy
Novel/kno
wn
coding variants
Novel/kno
wn no
n-‐coding variants
Targeted gene sequencing !" !" !" !" #" !"
SNP arraya #" !" !" #" #" !"
Array CGH #" !" !" !" !" !"
Exome #" !" !#" !#" #" !"
Whole Genome #" #" #" #" #" #"
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WGS500 Results
MENDELIAN Of 95 families, to date • 23 families have new clinical diagnosis
• NB pre-‐screened for known genes • result will increase with follow-‐up
• 74 families in follow up studies • Over 50% of these have strong lead candidate
• 7 Novel genes for disease • 6 Novel phenotypes for
known genes • 2 pathogenic regulatory variants in or downstream of known candidate genes • 6 genes missed by prior
Sanger Sequencing
WTCHG, Oxford: http://www.well.ox.ac.uk/wgs500
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• Rare disease with residual unmet diagnosEc need with a proband from the NHS in England
• Evidence of previous geneEc tesEng • ProspecEve collecEon but will include legacy collecEons • Family structures: ideally parent-‐offspring trios • Provision of Genomics England informed consent • Availability of clinical and further phenotypic data • Blood samples for DNA extracEon and mulE-‐omic samples
Rare Diseases – inclusion criteria
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• 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
Cancer – inclusion criteria
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• DiagnosEc reports that are accessible and meaningful • Dynamic serial reporEng -‐ evolving findings • Primary findings:
• Known pathogenic and expected pathogenic variants on known genes • Secondary “looked for” findings (currently for 10 condiEons):
• Strong cancers predisposiEon and familial hypercholesterolemia • For example Lynch syndrome, BRCA1/2, mulEple endocrine neoplasia
(MEN1), VHL • Carrier states of reproducEve importance (currently for 12 condiEons):
• Thalassemia, sickle cell, hemophilia A, …
• Read and variant level data accessible to NHS referring teams • PaEents can request genomic data files from Genomics England • PaEents are consented to be contacted up to four Emes a year
Feedback to the NHS
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Genomics England Pilots • Phase 1-‐ Sequencing and AnnotaEon CompeEEon • 4 providers 15 samples (5 tumour – normal pairs and 5 germline) • TesEng Sequencing QA and annotaEon
• Phase 2a-‐2000 Rare Inherited Disease WGS-‐ 30x depth – over 2014 • Partnering NIHR BioResource and TranslaEonal Research CollaboraEve • 5 centres -‐ 928 samples since end of November-‐ 1st 96 are in sequencing.
• Phase 2b-‐ 3000 Cancer PaEents (Lung, Breast, Ovary, Prostate & Colon) • SomaEc (?50-‐80x) and germline (30-‐40x) – tendering now • OpEmise Molecular Pathology pipeline • 11 CRUK Centres and BRCs
• Pathogens will be with Public Health England
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Process Overview
Clinical Interpretation
Variants (VCF)
Candidate Variants
Sequence (BAM)
Clinical Action
Sample DNA
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Process Overview Sample
DNA
Clinical Interpretation
Sequence Validation
Sequence (BAM)
Variants (VCF)
Variants (VCF)
Candidate Variants
Procured Sequence
Procured Annota@on
NHS
Clinical Interpretation
Clinical Action
GeL Database
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Sequencing and AnnotaEon assessment
• Sequencing bake-‐off – Samples sent to parEcipants; returned sequence assessed – EvaluaEon on quality and coverage – Informed sequencing contract
• AnnotaEon bake-‐off – Sequence sent to parEcipants (BAM+VCF)
• Rare diseases: trio • Cancer: germline + tumour
– Harder than assessing sequencing – Gold standard less well defined – Lack of established data standards
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ImplementaEon 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 InterpretaEon Partnership
(GeCIP) launched
• Biorepository: to be established
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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
hTp://www.england.nhs.uk/wp-‐content/uploads/2014/10/nhs-‐gmcs-‐stg2-‐iT-‐fin.pdf
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• East of England NHS GMC: Led by Cambridge University Hospitals NHS FoundaEon Trust;
• South London NHS: Led by Guy’s and St Thomas’ NHS FoundaEon Trust.
• North West Coast NHS GMC: Led by Liverpool Women’s NHS FoundaEon Trust.
• Greater Manchester NHS GMC: Led by Central Manchester University Hospitals NHS FoundaEon Trust
• University College London Partners NHS GMC: Led by Great Ormond Street Hospital NHS FoundaEon Trust
• North East and North Cumbria NHS GMC: Led by The Newcastle upon Tyne Hospitals NHS FoundaEon Trust.
• Oxford NHS GMC: Led by Oxford University Hospitals FoundaEon Trust.
• South West Peninsula NHS GMC: Led by Royal Devon & Exeter NHS FoundaEon Trust.
• Wessex NHS GMC: Led by University Hospital Southampton NHS FoundaEon Trust.
• Imperial College Health Partners NHS GMC: Led by Imperial College Healthcare NHS Trust.
• West Midlands NHS GMC: Led by University Hospitals Birmingham NHS FoundaEon Trust.
Eleven Genome Medicine Centres announced
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Genomics England – Proposed data flows
Clinical GeneEcs, Cancer & Public Health. NHS Trusts, PaEents & Public Pilots: Selected Centres, CRUK, BRCs Main Program: Genomic Medicine Centres
Safe haven:
Anonymised Clinical data and DNA sequence
Refreshable iden@fiable Clinical Data, linked to anonymised Whole Genome Sequence
Sequencing Centres
Sample repository
Clinicians & Academics Industry
Fire wall PaEent data stays on NHS side Only processed results pass outside
EHR Primary Care Hospital episodes
Sample
Clinical Report
AnnotaEon ‘Apps’
Pa3ent Consent
GeCIP
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Aims: • to opEmise clinical data and sample collecEon, clinical reporEng and data interpretaEon for return to clinicians and paEents
• to perform research to further improve our understanding of the implicaEons of the findings for genomic medicine in the clinical seung and
• to provide a rich training environment for trainees both within the Genomics EducaEon Programmes of Health EducaEon England.
Genomics England Clinical InterpretaEon Partnership -‐ GECIP
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• UK –led and self-‐organised into domains • Partnership with researchers, the NHS and Trainees. • Possible formaEon of a precompeEEve consorEum 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 diagnosEcs and therapies.
• Recognises that to get to a therapy will require significant addiEonal R&D which we aim to sEmulate here in the UK.
• IP owned by Genomics England but freely licensed
Genomics England Clinical InterpretaEon Partnership -‐ GECIP
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GeCIP Status and forward plans • Launched Wellcome trust 27th June 2014 • Call for Expressions of Interest and Guidance • Open meeEng and web cast 5th December 2014 • Work with potenEal GeCIP domains • Deadline for receipt of EOIs 26th January 2015 • Early February shaping final introductory GeCIPs • Mid-‐late February 2015 – announce introductory GeCIPs
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• 100,000 WGS of NHS paEents • Working with NHS, academics and industry to drive Genomic Medicine into the NHS
• Support that with educaEon • Leave a legacy of NGS Centres, sample pipeline and biorepository, large-‐scale data store that makes this usable by the NHS
• New diagnosEcs and therapies and opportuniEes for paEents
• By end of 2017
Genomics England
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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