the100,000genomesproject$ open... · 2015. 10. 19. · the100,000genomesproject$ tim hubbard...

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 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)

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/

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/

Genomics England

http://www.genomicsengland.co.uk/ @genomicsengland

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

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

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

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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

• 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

•  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

•  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

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

Process Overview

Clinical Interpretation

Variants (VCF)

Candidate Variants

Sequence (BAM)

Clinical Action

Sample DNA

Process Overview Sample

DNA


Sequence Validation

Sequence (BAM)

Variants (VCF)

Variants (VCF)

Candidate Variants

Procured Sequence

Procured Annota@on

NHS


Clinical Action

GeL Database

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

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

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

•  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

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

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

•  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

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

•  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

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

the100,000genomesproject$ open... · 2015. 10. 19. · the100,000genomesproject$ tim hubbard...

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