The Genomics England 100,000 Genomes Project...2005/10/17 · Nevin-Ridley1, Olivia Niblock1,...
Transcript of The Genomics England 100,000 Genomes Project...2005/10/17 · Nevin-Ridley1, Olivia Niblock1,...
Confidential: For Review Only
The Genomics England 100,000 Genomes Project
Journal: BMJ
Manuscript ID BMJ.2017.041782
Article Type: Analysis
BMJ Journal: BMJ
Date Submitted by the Author: 05-Oct-2017
Complete List of Authors: Turnbull, Clare; Queen Mary University of London, William Harvey Research Institute; Institute of Cancer Research, Boardman-Pretty, Freya; Genomics England Scott, Richard; Genomics England; Great Ormond Street Hospital NHS Trust Thomas, Ellen; Genomics England; Guys and St Thomas NHS Foundation Trust Halai, Dina; Genomics England Jones, Louise; Genomics England; Barts Cancer Institute, Queen Mary University of London
Murugaesu, Nirupa; Genomics England; St George's University Hospitals NHS Foundation Trust O’Neill, Amanda; Genomics England; University of Cambridge Henderson, Shirley; Genomics England; Oxford Universities NHS FoundationTrust Devereau, Andrew; Genomics England Hamblin, Angela; Genomics England; Oxford Universities NHS FoundationTrust Patch, Christine; Genomics England; Guys and St Thomas NHS Foundation Trust Baple, Emma; Genomics England; University of Exeter Mason, Joanne; Genomics England
Smith, Katherine; Genomics England Rueda-Martin, Antonio; Genomics England Ryten, Mina; Genomics England; University College London Lawson, Kay; Genomics England Smedley, Damian; Genomics England; Queen Mary University of London, William Harvey Research Institute Antoniou, Pavlos; Genomics England Athanasopoulou, Maria; Genomics England Boustred, Chris; Genomics England Brittain, Helen; Genomics England Campbell, Chris; Genomics England
Coll-Moragon, Jacobo; Genomics England Craig, Clare; Genomics England Cranage, Alison; Genomics England Daugherty, Louise; Genomics England
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Confidential: For Review OnlyDinh, Lisa; Genomics England Foulger, Rebecca; Genomics England Furio-Tari, Pedro; Genomics England Garikano, Kristina; Genomics England Goddard, Peter; Genomics England Gordon, Duncan; Genomics England Hackett, Joanne; Genomics England Hatwal, Atul; Genomics England Hubble, Samuel; Genomics England
Jackson, Rob; Genomics England Jang, Mikyung; Genomics England Kasperaviciute, Dalia; Genomics England Leigh, Sarah; Genomics England Logie, Cameron; Genomics England Lopez, Javier; Genomics England McDonagh, Ellen; Genomics England McGrath, Kenan; Genomics England Medina, Ignacio; Genomics England Mueller, Michael; Genomics England Nevin-Ridley, Katrina; Genomics England Niblock, Olivia; Genomics England
Ocampo, Ernesto; Genomics England Parker, Matthew; Genomics England Prapa, Matina; Genomics England Riley, Laura; Genomics England Rimmer , Andy; Genomics England Rogers, Tim; Genomics England Serra, Enric; Genomics England Shallcross, Laura; Genomics England; University College London, Department of Infection and Population Health Sosinsky, Alona; Genomics England Stals, Karen; Genomics England
Sultana, Razvan; Genomics England Thompson, Simon; Genomics England Tregidgo, Carolyn; Genomics England Tucci, Arianna; Genomics England Tuff-Lacey, Alice; Genomics England Witkowska, Katarzyna; Genomics England; Queen Mary University of London, William Harvey Research Institute Mahon-Pearson, Jeanna; Genomics England Bale, Mark; Genomics England Fowler, Tom; Genomics England Hubbard, Tim; Genomics England; Kings College London, Medical and Molecular Genetics
Rendon, Augusto; Genomics England; University of Cambridge Caulfield, Mark; Genomics England; Queen Mary University of London, William Harvey Research Institute
Keywords: Whole Genome Sequencing, Next Generation Sequencing, Rare Disease, Cancer Genomics, Secondary Findings
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Confidential: For Review OnlyThe Genomics England 100,000 Genomes Project
Clare Turnbull1-4
, Freya Boardman Pretty1¸Richard Scott
1,5, Ellen Thomas
1,2, Dina Halai
1, Louise Jones
1,6, Nirupa
Murugaesu1,7
, Amanda O’Neill1,10
, Shirley Henderson1,11
, Andrew Devereaux1, Angela Hamblin
1,11, Christine
Patch1,2,12
, Emma Baple1,9
, Joanne Mason1, Katherine Smith
1, Antonio Rueda Martin
1, Mina Ryten
1,2,8, Kay
Lawson1, Damian Smedley
1,3, Pavlos Antoniou
1, Maria Athanasopoulou
1, Chris Boustred
1, Helen Brittain
1, Chris
Campbell1, Jacobo Coll Moragon
1, Clare Craig
1, Alison Cranage
1, Louise Daugherty
1, Lisa Dinh
1, Rebecca
Foulger1, Pedro Furio Tari
1, Kristina Garikano
1, Peter Goddard
1, Duncan Gordon
1, Joanna Hackett
1, Atul
Hatwal1, Samuel Hubble
1, Rob Jackson
1, Mikyung Jang
1, Dalia Kasperaviciute
1, Sarah Leigh
1, Cameron
Logie1, Javier Lopez
1, Ellen M. McDonagh
1, Kenan McGrath
1, Ignacio Medina
1, Michael Mueller
1, Katrina
Nevin-Ridley1, Olivia Niblock
1, Ernesto Ocampo
1, Matthew Parker
1, Matina Prapa
1, Laura Riley
1, Andy
Rimmer1, Tim Roger
1, Enric Serra
1, Laura Shallcross
1, Alona Sosinsky
1, Karen Stals
1, Razvan Sultana
1, Simon
Thompson1, Carolyn Tregidgo
1, Arianna Tucci
1, Alice Tuff-Lacey
1, Katarzyna Witkowska
1, Jeanna Mahon-
Pearson1, Mark Bale
1, Tom Fowler
1, Tim Hubbard
1,14, Augusto Rendon
1,10, Mark Caulfield
1,3
1 Genomics England, Charterhouse Square, London, EC1M 6BQ
2 Guys and St Thomas NHS Foundation Trust, London, SE1 9RT.
3 William Harvey Research Institute, Queen Mary University of London, EC1M 6BQ
4 Institute of Cancer Research, London, SM2 5NG.
5 Great Ormond Street Hospital NHS Trust, London, WC1N 3JH
6 Barts Cancer Institute, Queen Mary University of London, EC1M 6BQ
7 St George's University Hospitals NHS Foundation Trust, London SW17 0QT.
8 University College London, Gower Street, London, WC1E 6BT
9 University of Exeter, Exeter, EX4 4SB.
10 University of Cambridge, Cambridge, CB2 1TN.
11 Oxford Universities NHS Foundation Trust, Oxford, OX3 9DU.
12 Florence Nightingale Faculty of Nursing & Midwifery, King’s College, London SE1 8WA.
13 University of Oxford, Oxford, OX1 2JD.
14 Medical and Molecular Genetics, Kings College London, WC2R 2LS.
On behalf of the 100,000 Genomes Project
Word count: 2471
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Confidential: For Review OnlyAbstract
The 100,000 Genomes Project is a government-led initiative to sequence 100,000 whole genomes from
patients recruited from the National Health Service (NHS) in England. The project was established to develop
the infrastructure and expertise necessary to transform delivery of genomic medicine into the NHS, to deliver
benefit to patients, to enable high quality research and to boost the UK genomics industry.
Background
The UK has long been at the forefront of human genomics, from descriptions in the 1950s by Franklin, Watson
and Crick of the 3D structure of DNA through to early development by Cambridge scientists of the technology
for solid phase colony sequencing that underpins current next-generation sequencing (box a)1. Sequencing of
the first human genome, delivered collaboratively by 20 research sequencing centres through The Human
Genome Project, took 13 years and cost an estimated $3 billion2 3
. Recent advances in next-generation
sequencing (NGS) have enabled ‘massively parallel’ simultaneous sequencing of millions of fragments of DNA
such that a whole genome can be now be sequenced in less than a day at a cost of less than $1,000 (and
falling, fig a)4.
This technological renaissance offers dramatic opportunities for more widespread applications of genomics in
healthcare. Our increasing understanding of how molecular (genomic) changes correlate with clinical
diagnosis, prognosis, risk and/or therapeutic response is making more possible the delivery of so-called
‘precision’, ‘personalised’, or ‘stratified’ medicine (box b)5 6
.
The UK has a mature network of Regional Genetics Laboratories and Clinical Genetics departments,
established over the last 30 years. However, as highlighted in genomics strategy reports from the House of
Commons Science and Technology Committee, the Human Genome Strategy Group and the Chief Medical
Officer (CMO), considerable transformation of NHS genomics services is required to truly capitalise upon the
opportunities afforded by the revolution in genomic technologies for more accurate and cost-effective
healthcare7-9
. Needs repeatedly highlighted are (i) establishing high-throughput, cost-effective large-scale
sequencing capacity; (ii) developing consistent, quality-assured pipelines for data processing, analysis,
interpretation and storage of data (iii) capturing of clinical data of consistent quality and format; (iv) improving
equity of patient access to genomic services and; (v) centralised storage of linked clinical and molecular data10-
12. Furthermore, review of policies around consent, data federation and data security are urgently required.
This is key to ensuring that the nationally streamlined genomic data resource can be used across the ‘virtual
laboratory of the NHS’ to optimise real time clinical genomic interpretation for patients, whilst also enabling
access by researchers from academia and industry to advance genomic understanding in the longer term8. As
well as increasing genetic literacy across the entire clinical workforce, it was highlighted that urgent workforce
expansion was required in specific areas such as clinical bioinformatics. Furthermore, the role of clinical
scientists is expanding as their remit expands to include advanced computing skills, in addition to the
established laboratory proficiencies8.
Initiation of the 100,000 Genomes Project
In December 2012, then Prime Minister the Right Honourable David Cameron announced that as part of the
Olympic Legacy funding would be committed to sequence 100,000 genomes from patients in the English NHS.
As well as catalysing transformation of NHS genomics, key objectives were to deliver benefit for patients,
stimulate research and industry and to evolve public trust through transparency (box c). Genomics England
was created to deliver the project, funded by the National Institute for Health Research (NIHR) with the
Department of Health as the sole shareholder of the company. Substantial contributions to the programme
also came from NHS England, Public Health England and Health Education England, with additional support
from the Wellcome Trust, Medical Research Council and Cancer Research UK (box d). Rare disease and cancer
were agreed as the initial priority areas 13
.
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Setting up the 100,000 Genomes Project through partnership
Genomics Medicine Centres as hubs of expertise in the NHS
In 2014, NHS trusts were invited to tender to become NHS Genomic Medicine Centres (GMCs): regional hubs
of excellence in genomic medicine through which existing expertise in molecular genetics, molecular
pathology, clinical genetics services and molecular oncology would be grown. Following two rounds of
evaluation, 13 NHS Genomic Medicine Centres have now been established, each comprising a lead NHS trust
and up to 12 local delivery partner hospitals. In total the NHS GMC network comprises over 85 hospital trusts
and provides full geographic coverage of England (Fig b). In addition, Northern Ireland and Wales are
developing capabilities as Genomic Medicine Centres and Scotland has a parallel sequencing project in
collaboration with Genomics England.
Harnessing the expertise of the research community through the Genomics England Clinical Interpretation
Partnership (GeCIP)
To leverage the wealth of genomic expertise across the UK clinical academic community, the Genomics
England Clinical Interpretation Partnership (GeCIP) was established. Following a call for expressions of interest,
>2600 researchers, comprising >2300 UK-based academics and NHS clinicians and >280 international
collaborators, spanning 343 institutions worldwide, responded and self-organised into 41 domains. These
domains span rare disease, tumour types and cross-cutting themes such as ethics, health economics and
advanced analytical approaches (fig c)14 15
. GeCIP researchers have been providing expert support in clinical
interpretation of the genomes and in return are receiving priority access to deidentified genome data via
research data embassies: a quid pro quo partnership (fig d).
Partnering with and stimulating the Genomics Industry in the UK
Following a competitive tender between multiple sequencing providers, in 2014 Illumina was selected to
partner with the programme to provide sequencing services. 29 suppliers of genomic analysis, annotation and
interpretation services were also evaluated, a subset of which have become 'clinical interpretation partners',
supplying decision support software and variant prioritisation algorithms for use by the NHS GMCs. In parallel,
Genomics England, in partnership with Innovate UK, awarded £10 million of forward investment via the Small
Business Research Initiative (SBRI) to 9 companies with the most promising proposals to further develop
genome annotation tools and services.
Sequencing infrastructure and data architecture to deliver a national genomics service
Supported by the Wellcome Trust, housed in the Bridget Ogilvie building, the 100,000 Genomes Project
Sequencing Centre was built at the Wellcome Genome Campus in Hinxton, Cambridgeshire, with capacity to
deliver >12,000 whole genome sequences (WGS) per week. Rigorous data security being paramount, the
100,000 Genomes Project data are stored in the highly secure government data centre in Corsham, utilising
strict systems for data permissions and access. Robustly-tested, versioned pipelines for data processing and
analysis have been established to ensure reliable and reproducible genomic analyses for return to the
clinicians and patients, with ISO 15189 (medical laboratory accreditation) of the sample and data pipelines
underway. While identifiable clinical and molecular data are returned to clinicians from NHS GMCs, de-
identified instances of the data are available in a secure Research Environment for approved researchers from
academia and industry (fig d).
Education and Training
In partnership with Health Education England (HEE), £20 million has been directed towards development of
educational resources and training opportunities delivered in parallel with the 100,000 Genomes Project.
Masters courses in Genomic Medicine have been established at 10 universities, with 446 having enrolled in the
full Masters to date with hundreds more enrolling in the PGCert, PGDip or individual modules. Funding has
been committed through to 202316
. A new Genomic Counsellor Masters and training programme was
established in 2016, through which 25 additional genetic/genomic counsellors are already being trained. HEE
research fellowships in genomics were awarded in 2017, with >£1.3 million awarded to 9 applicants. Online
training resources such as MOOCs (Massive Open Online Courses) have been developed for the broader
clinical workforce in areas such as consent, bioinformatics and molecular pathology 17 18
.
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Patient and Public Involvement (PPI)
Open town-hall style events held at inception of the project have enabled stakeholder groups, patients and the
public to aid in sculpting the programme19-21
. A national participant panel convening bimonthly also provides
representation to the Data Access Committee, Ethics Advisory Committee and GeCIP Board22
. As part of the
Genomics England Engagement Strategy, in 2016 a programme of activities – the Genomics Conversation –
was rolled out through a broad range of activities, including debates, discussions, presentations, and outreach
through social and traditional media23
.
Clinical pathways for patients, samples and data
The Rare Disease Programme
There are >200 phenotypic categories by which patients are eligible for recruitment to the Rare Disease
programme, which span over half of the >7000 OMIM disorders described (fig e)24
. These categories were
nominated by the clinical community on account of being underserved by current clinical diagnostic testing,
and/or because the genetic basis of the disorder required further elucidation through research25-29
. Eligibility
for each category is defined by a set of clinical and/or family characteristics, pre-testing of well-established
genes and an optimal family structure for recruitment (typically (i) trio including unaffected parents, (ii) multi-
generational affected individuals or (iii) isolated proband in later onset disorders). The analysed genomic
variants, ‘tiered’ for disease-causing potential based on allele frequency, familial inheritance, variant impact
and gene-phenotype association using ‘virtual panels’ of genes, are returned via decision-support tools. First
review is undertaken by clinical scientists at NHS GMC laboratories, followed by clinical interpretation at
local/regional genomic Multidisciplinary meetings (MDMs)30
.
The Cancer Programme
For the Cancer Programme, patients with a range of solid tumours and haematological malignancies are
eligible for recruitment at primary diagnosis. Whole genome sequencing is undertaken on paired constitutional
DNA derived from blood/saliva and tumour DNA derived from biopsy or surgical resection24
. Additional insights
around molecular determinant of response, progression and metastasis will be afforded from alignment of
recruitment to clinical studies and trials and collection of longitudinal and multi-region tumour samples.
Lifelong linkage will enable longitudinal clinical data capture on treatment, response and outcomes, including
ENCORE, COSD, SACT and RTDS datasets from the Cancer Registration service, as well as HES and ONS data31-35
(fig h). Serial blood samples are also being captured for the analysis of circulating tumour DNA (ctDNA)36
.
Analysed genomes are returned via interactive web-based formats for review at NHS GMC ‘tumour sequencing
boards’. Variants are annotated for potential diagnostic, predictive or prognostic ‘actionability’. The results
returned are annotated for (i) well-characterised mutations marking eligibility for NICE-approved targeted
drugs such as BRAF-inhibitors in melanoma and EGFR inhibitors in lung cancer (ii) other gene mutations,
fusions and copy number changes for clinical trials of experimental molecules are available (iii) analyses of
signatures and mutational burden which are emerging as clinical biomarkers of drug response.
Progress and performance
Piloting of patient recruitment, sample collection, sequencing and data analysis was initiated in 2013 for both
the rare disease (4957 participants) and cancer programmes (1650 participants). The first patients from the
NHS GMCs were recruited in February 2015, with an average weekly recruitment of ~650 participants and
cumulative recruitment of 46,698 participants by October 2017 (fig e).
Sequencing at the 100,000 Genomes Project Sequencing centre in Hinxton commenced in March 2016; by
October 2017, a cumulative total of 36,083 WGS had been generated. Constitutional samples are being
sequenced to produce a minimum of 85 GB of data per sample (>300 million high quality, non-duplicated
sequencing reads per samples ensuring at least 15 sequencing read coverage for over 90% of the 3.2 billion
bases in each patient genome, figs f and g).
In March 2015, the first pilot results were returned to a family from Newcastle who had unexplained
autosomal dominant pattern renal failure: identification of a pathogenic INF2 mutation has enabled more
targeted blood pressure control in family members with early disease, whilst taking family members without
the mutation out of lifelong follow-up and anxiety. By October 2017, results had been returned to 4426 NHS
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Confidential: For Review Only
participants with a preliminary diagnostic rate of 22%. This diagnostic yield (whole genome sequencing
following standard of care testing) is comparable to other sequencing projects but will likely further increase
following additional local clinical review of untiered variants and subsequent reporting of mutational classes
beyond small variants37 38
.
Challenges, hurdles and future directions
Hurdles initially limiting to recruitment have stimulated collaborative work to develop solutions and novel
approaches (box e). Fresh tumour tissue, while providing molecular results of dramatically higher quality (in
particular for whole genome sequencing), has to date almost exclusively been the preserve of research
studies. Acquisition, processing, storage and transport of fresh tumour tissue across the diverse cancer
pathways (involving theatres, out-patients, endoscopy, interventional radiology) has driven evolution of new
practices including vacuum-packing, tissue refrigeration, novel coolants and transport media. Furthermore,
significant simplification of consent within these complex pathways has been achieved through establishing a
joint statement that collection of fresh tissue as standard of care in modern cancer diagnostics, signed by the
Royal College of Pathology, NHS England, Genomics England, the Human Tissue Authority and Health Research
Authority39
.
This programme has required timely, accurate, complete submission of data on clinical features, sample
handling and sample tracking using unified data ontologies and models40 41
. Significant heterogeneity in the
quality of local data capture and storage has emerged, along with the degree of pressure upon local
informatics resource and expertise. Collaborative approaches across trusts working with NHS Digital, NHSE,
and the Farr Institute has driven solutions such as the GENIE system developed by the West Midlands NHS
GMC, which automates capture, collation and delivery of clinical and sample data from diverse systems42
. In
collaboration with the Association for Clinical Genetic Science, Genomics England and NHS England have co-led
development of cross-GMC multi-disciplinary expert working groups, which are evolving evidence-based, pan-
NHS standards for variant interpretation, technical validation, quality assurance and clinical reporting,
addressing substantial historical inconsistencies in these areas.
Genomics England and NHS England are co-leading transition working groups to evolve evidence-based
frameworks to direct NHS commissioning of genomic testing (including whole genome sequencing) post-2018.
Based on systematic clinical and health-economic evaluation, there will be directories of genetic tests linked to
a national ‘order-comms’ system, ensuring equity of patient access and consistency of testing provision.
Genomic testing will be delivered through (i) a centralised infrastructure for whole genome sequencing
established by Genomics England linked to (ii) a consolidated network of NHS England Genomic Laboratory
Regional Genetics Hubs, re-procurement of which is underway. This will be managed by a centralised NHS
England Genomics Coordinating Centre. Through evolution of these infrastructures, along with an expanded
specialist workforce and an upskilled general workforce, the Genomics England 100,000 Genomes Project will
have been a key catalyst to the delivery of a truly modernised UK genomics service43 44
.
Box a: Landmarks in UK genomic research
1903: pioneering studies of early inborn errors of metabolism by Archibald Garrod at University
College London, later Oxford
1951: X-ray diffraction studies reveal 3D structure of DNA, Rosalind Franklin, King’s College
London
1953: elucidation of the structure of the double helix by James Watson and Francis Crick,
Cambridge University
1954: description of the structure and synthesis of nucleotides and nucleosides by Alexander
Todd, Cambridge University
1977: ‘chain-termination’ sequencing by synthesis is developed by Frederick Sanger and Alan
Coulson, Cambridge University
1990: scientists from Wellcome Trust Sanger Centre lead UK Human Genome Project effort
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Confidential: For Review Only1995: development of solid phase colony next-generation sequencing technology at Cambridge
University
Box b: Application of genomics for healthcare improvement
• Diagnosis of rare and/or inherited diseases: whole genome or exome sequencing for a child
with rare disease within the first weeks or months of life enables provision of a precise
molecular genetic diagnosis. This offers opportunity for early administration of the
interventions and therapies most likely to be effective, improved estimation of prognosis, pre-
emption of complications and, if timely, facilitates reproductive decision-making for
subsequent pregnancies. Historically diagnosis in rare disease took, on average, seven years.
A ‘diagnostic odyssey’ was typical, involving investigation of multiple organ systems by
different medical specialists and, even once referred to a geneticist, prolonged, serial testing
of individual genes.
• Non-invasive pre-natal testing: analysis of fetal DNA circulating in the maternal bloodstream
is transforming population screening for conditions such as Down’s syndrome. Genetic testing
in pregnancy for known conditions can also be undertaken non-invasively, avoiding the risk of
amniocentesis or CVS (chorionic villus sampling).
• Newborn screening: newborn screening has to date relied on assay of relevant metabolites to
detect severe inherited diseases. Sequencing of the relevant genes may enable earlier and
more accurate detection at a population level of childhood diseases.
• Testing for carrier status for genetic diseases: identification in the population of individuals
or couples at high risk of having a child with a severe genetic disease enables reproductive
options such as preimplantation genetic diagnosis to be offered.
• Risk stratified cancer screening: identification in the population of well individuals at high
inherited genetic risk of developing cancer allows targeting of early interventions such as
intensive screening, preventative drugs and risk-reducing surgery.
• Drug sensitivity and metabolism: analysis for ‘pharmacogenomic’ variants can enable
avoidance of life-threatening toxicity from chemotherapeutic drugs and precision dosing in
widely-used drugs such as warfarin45.
• Early detection of cancer: analysis of peripheral blood for circulating tumour DNA (ctDNA) is
offering new opportunities for non-invasive surveillance for cancer recurrence. Large scale
research programmes are underway to evaluate the role of ctDNA in primary population
screening for cancer36.
• Precision oncology and targeted cancer treatments: growth and replication of cancer cells
can be driven by mutated oncogenes (‘oncogene addiction’)46
. Small molecules or monoclonal
antibodies switching off the over-active protein can yield dramatic response (targeted drugs).
However, the response is often time-limited as the tumour typically evolves a ‘resistance
mutation’.
• Rapid detection of pathogens and characterisation of resistance: sequencing of viral and
bacterial genomes enables delineation of species taxonomy, virulence, transmission and anti-
microbial resistance47.
Box c: Key objectives of the 100,000 Genomes Project
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Confidential: For Review Only1. To bring benefit to NHS patients through transformation of NHS genomics services
2. To create an ethical and transparent programme based on consent
3. To enable new scientific discovery and medical insights
4. To kick start the development of a UK genomics industry
Box d: Major funding support for the 100,000 Genomes Project
Government/NIHR: £300 million
MRC: £24 million - for computing infrastructure, plus £12.1 million supporting the devolved
nations
Wellcome Trust: £27 million-for the 100,000 Genomes Project Sequencing Centre
NHSE: £20 million
Box e: 100,000 Genomes Project: examples of early steps in catalysing complex change
1) Complexity around consent. As per introduction to the NHS of any paradigm-shifting
technology, this programme is a hybrid of clinical care and research, causing tensions around
consent. Research consent addresses sharing data with researchers from industry as well as
life-long data storage and linkage, both areas of potential public concern. Impact on insurance
and longer-term diminution in mental capacity need to be covered when enrolling participants.
Children and teenagers are alerted that they will require re-consenting on turning 18. We are
also piloting return of secondary findings (genetic variants identified which are not related to
the condition under investigation but which are informative to the risk of unrelated but serious
medical conditions)48 49. The time required offer informed consent for all these complex
aspects, along with collecting all clinical/phenotype data, has rendered infeasible recruitment
within a routine outpatient setting.
2) Tensions between data protection and federation. Only through comparing across patients’
phenotypes and their genomes in cases of rare disease can we correctly narrow down from the
millions of variants in the genome to the single causative pathogenic rare variant. Therefore,
sharing data across the ‘virtual laboratory of the NHS’ is essential; sharing internationally
through clinical networks such as DeCIPHER50 51 and Matchmaker52 53 further increases
opportunity for ‘matching’ genotypes with other patients with similar vanishingly rare disease.
3) Collection of phenotype data. Genomic interpretation and/or subsequent research for
individuals with rare disease requires detailed capture of phenotypic elements in a universal
hierarchical ontology, for which the HPO (Human Phenotype Ontology) has largely been
adopted internationally40 54. Preliminary systems for capturing HPO terms have been
implemented for this project (fig h), but are otherwise currently entirely lacking within routine
electronic medical records and other NHS data systems.
4) ‘Mainstreaming’ and democratisation of the genome. Germline genetic testing has to date
largely been the preserve of Clinical Geneticists. This programme has catalysed the expansion
of genomics into other medical specialties, but highlighted that judicious oversight across this
larger and more diverse range of clinicians will be required to ensure the appropriate genomic
test is applied to a patient/family, along with detailed and accurate capture of phenotyping
and proportionate interpretation of complex genomic results.
5) Unpicking genotype-phenotype inferences. Large-scale genomic sequencing applied to
broader patient groups is disrupting established genotype-phenotype paradigms, derived from
targeted gene sequencing in original families ascertained with classical phenotypes. A
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Confidential: For Review Onlypathogenic variant may be detected on WGS, but careful clinical review is required to establish
the degree to which the variant explains the phenotype in the patient and any additional
implications for health. The programme has triggered development of specialty genomic-
MDMs in areas such as ophthalmology, cardiology and neurology at which laboratory clinical
scientists, clinical geneticists, disease specialists and expert researchers convene.
6) Molecular pathology. Routine acquisition of fresh frozen tissue (surgical and biopsy) along
with pathology evaluation for sample tumour purity has required re-engineering of hundreds
of cancer ‘pathways’, which vary tumour type-to-tumour type and trust-to-trust.
7) Tumour Sequencing Boards (TSBs). GMCs are establishing Tumour Sequencing Boards for
review of cancer WGS with representation from molecular pathology, molecular oncology and
clinical trialists. Sophisticated hub-and-spoke networks have evolved to facilitate information
flow from molecular experts to tumour-types-specific MDT meetings, across complex
geography in a time-scales relevant to cancer management.
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Figure a: The decrease in cost of sequencing against time
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Figure b: 13 Genomic Medicine Centres have been established, each with a lead
organisation, encompassing >85 NHS trusts. Roles of GMCs include:
• identification of patients eligible for whole genome sequencing, with equity
of access through established eligibility
• criteria
• consenting of patients and collection of clinical data.
• collection of biological samples (blood/tumour tissue/saliva)
• sample processing, DNA extraction and quality control checks
• sample dispatch to the central sample biorepository
• interpretation and technical validation of clinically important variants
• return of genomic findings to patients and implementation of management
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Rare Disease Cancer Cross-cutting
• Cardiovascular
• Dermatology
• Endocrine and
Metabolism
• Gastroenterology and
Hepatology
• Haematology
• Hearing and Sight
• Immunology
• Inherited Cancer
Predisposition
• Musculoskeletal
• Neurology
• Paediatric sepsis
• Paediatrics
• Renal
• Brain Tumours
• Breast Cancer
• Cancer of Unknown Primary
• Childhood Solid Cancers
• Colorectal Cancer
• Haematological Malignancy
• Head and Neck Cancer
• Lung Cancer
• Melanoma
• Neuroendocrine Tumours
• Ovarian and Endometrial Cancers
• Pan-Cancer
• Prostate Cancer
• Renal and Bladder Cancers
• Sarcoma
• Testicular Germ Cell Tumours
• Education and Training
• Electronic Health Records
• Enabling Rare Disease
Translational Genomics
via Advanced Analytics
and International
Interoperability
• Ethics and Social Science
• Functional Cross-Cutting
• Functional Effects
• Health Economics
• Machine Learning,
Quantitative Methods
and Functional Genomics
• Population Genomics
• Stratified Medicine and
Therapeutic Innovation
Figure c: The Genomics England Clinical Interpretation Partnership: Researchers have grouped themselves
into 41 “domains” and will work within these groups to analyse the genomic and clinical data to make
additional diagnoses in patients and advance overall genomic understanding
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Figure d: Data flow in the 100,000 Genomes Project
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Figure e: Current total families recruited to the Rare Disease arm of the Project, by disease category
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Figure f: Number of WGS returned to Genomics England from Illumina from the beginning of the Project.
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Figure g: per base sequencing coverage for constitutional (blood) from a sample of sequences
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Figure h: Number of overall and positive HPO terms per participant, for all participants in the rare disease
arm of the programme with at least one HPO term entered.
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Figure i:
(a) Number of HES records by date for all current project participants.
(b) Total HES records for all project participants, by source (log scale).
(c) Total records held for project participants, by external data set (log scale).
(HES: Hospital Episode Statistics; DID: Diagnostic Imaging Dataset; PROMs: Patient Reported Outcome
Measures; ONS: Office for National Statistics)
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Confidential: For Review OnlyContribution
The manuscript was drafted by CT with support from MC, FBP, RS, ET, DH, LJ, AR, KS, TH and JM. All
authors contributed to the project and reviewed the final manuscript.
Conflicts of interest
We have read and understood the BMJ Group policy on declaration of interests and declare the
following interests: none.
License
Clare Turnbull, The Corresponding Author has the right to grant on behalf of all authors and does
grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a
worldwide basis to the BMJ Publishing Group Ltd ("BMJ"), and its Licensees to permit this article (if
accepted) to be published in The BMJ's editions and any other BMJ products and to exploit all
subsidiary rights, as set out at: http://www.bmj.com/about-bmj/resources-authors/forms-policies-
and-checklists/copyright-open-access-and-permission-reuse.
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References
1. Heather JM, Chain B. The sequence of sequencers: The history of sequencing DNA. Genomics
2016;107(1):1-8. doi: 10.1016/j.ygeno.2015.11.003 [published Online First: 2015/11/12]
2. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature
2001;409(6822):860-921. doi: 10.1038/35057062 [published Online First: 2001/03/10]
3. Finishing the euchromatic sequence of the human genome. Nature 2004;431(7011):931-45. doi:
10.1038/nature03001 [published Online First: 2004/10/22]
4. Hayden EC. Technology: The $1,000 genome. Nature 2014;507(7492):294-5. doi:
10.1038/507294a [published Online First: 2014/03/22]
5. Ashley EA. Towards precision medicine. Nat Rev Genet 2016;17(9):507-22. doi:
10.1038/nrg.2016.86 [published Online First: 2016/08/17]
6. Hutchison CA, 3rd. DNA sequencing: bench to bedside and beyond. Nucleic Acids Res
2007;35(18):6227-37. doi: 10.1093/nar/gkm688 [published Online First: 2007/09/15]
7. Genomic Medicine: Science & Technology Committee Report.
https://hansard.parliament.uk/Lords/2010-06-
09/debates/10060963000015/GenomicMedicineSAndTCommitteeReport, 2010.
8. Office of the Chief Medical Officer DoH. Annual Report of the Chief Medical Officer 2016:
Generation Genome. 2017
9. Building on our inheritance: Genomic technology in healthcare Human Genomics Strategy Group,
2012.
10. Molecular diagnostic provision in England: For targeted cancer medicines (solid tumour) in the
NHS: Cancer Research UK, 2015.
11. Improving Outcomes: A Strategy for Cancer: Department of Health, 2011.
12. Ensuring equitable access to complex molecular diagnostic testing for cancer patients:
Department of Health, 2012.
13. Lomas DA. Strategic Priorities for 100,000 Genomes Project, 2013.
14. Marx V. The DNA of a nation. Nature 2015;524(7566):503-5. doi: 10.1038/524503a [published
Online First: 2015/08/28]
15. The Genomics England Clinical Interpretation Partnership. Nature, 2014.
16. Genomics Education Programme: Health Education England, 2015.
17. The Genomics Era: the Future of Genetics in Medicine: St Georges University of London, 2015.
18. Tumour Assessment for Whole Genome Sequencing: Health Education England, 2016.
19. Earning Trust. Public Engagement and Patient Involvement Strategy 2015-17: Genomics England,
2015.
20. What do patients with rare genetic conditions think about whole genome sequencing in the
NHS? Research Findings for the 100,000 Genomes Project: Genetic Alliance UK, 2014.
21. Ethical issues relating to involvement of cancer patients in the 100,000 genomes project:
Genomics England, 2014.
22. Call for members of new Participant Panel [Available from:
https://www.genomicsengland.co.uk/participant-panel/.]
23. Parry V. A Year of Conversations about Genomics 2014 [Available from:
https://www.genomicsengland.co.uk/a-year-of-conversations-about-genomics/.]
24. The 100,000 Genomes Project Protocol: Genomics England, 2015.
25. Rare Disease UK [Available from: https://www.raredisease.org.uk/what-is-a-rare-disease/.]
26. Inserm Ophanet: Portal for rare diseases and orphan drugs [updated 6/10/2016. Available from:
http://www.orpha.net/consor/cgi-bin/index.php.]
27. Commission expert group on rare diseases: European Commission, 2016.
28. The UK Strategy for Rare Diseases: Department of Health, 2013.
29. International Rare Diseases Research Consortium: Policies and Guidelines, 2013.
Page 20 of 25
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only30. Genomics England: PanelApp 2016 [Available from:
https://panelapp.extge.co.uk/crowdsourcing/PanelApp/.]
31. Progress in improving cancer services and outcomes in England: National Audit Office, 2015.
32. Cancer Registration Statistics, England: 2014. Cancer diagnoses and age-standardised incidence
rates for all cancer sites by age, sex and region.: Office For National Statistics, 2014.
33. Cancer Outcomes and Services Dataset (COSD) 2016 [Available from:
http://www.ncin.org.uk/collecting_and_using_data/data_collection/cosd.]
34. Public Health England: National Radiotherapy Dataset (RTDS) 2016 [Available from:
http://www.ncin.org.uk/collecting_and_using_data/rtds.]
35. NHS Digital: Hospital Episode Statistics 2016 [Available from: http://content.digital.nhs.uk/hes.]
36. O'Leary B, Turner NC. Science in Focus: Circulating Tumour DNA as a Liquid Biopsy. Clin Oncol (R
Coll Radiol) 2016 doi: 10.1016/j.clon.2016.08.007 [published Online First: 2016/10/09]
37. Stavropoulos DJ, Merico D, Jobling R, et al. Whole Genome Sequencing Expands Diagnostic Utility
and Improves Clinical Management in Pediatric Medicine. NPJ Genom Med 2016;1 doi:
10.1038/npjgenmed.2015.12 [published Online First: 2016/01/13]
38. Lionel AC, Costain G, Monfared N, et al. Improved diagnostic yield compared with targeted gene
sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.
Genet Med 2017 doi: 10.1038/gim.2017.119 [published Online First: 2017/08/05]
39. England G. Consensus Statement Diagnostic pathways for NHS cancer genomic sampling and
analysis. https://www.genomicsengland.co.uk/information-for-gmc-staff/cancer-
programme/cancer-programme-documentation/, 2017.
40. Kohler S, Doelken SC, Mungall CJ, et al. The Human Phenotype Ontology project: linking
molecular biology and disease through phenotype data. Nucleic Acids Res 2014;42(Database
issue):D966-74. doi: 10.1093/nar/gkt1026 [published Online First: 2013/11/13]
41. Human Phenotype Ontology: New HPO Release [updated September 3, 2016. Available from:
http://human-phenotype-ontology.github.io/.]
42. The Farr Institute [Available from: http://www.farrinstitute.org/about.]
43. Keogh B. Personalised Medicine Strategy: NHS England Board, 2015.
44. Improving outcomes through personalised medicine: Working at the cutting edge of science to
improve patients’ lives: NHS England, 2016.
45. Pirmohamed M. Personalized pharmacogenomics: predicting efficacy and adverse drug
reactions. Annu Rev Genomics Hum Genet 2014;15:349-70. doi: 10.1146/annurev-genom-
090413-025419 [published Online First: 2014/06/06]
46. Schmidt KT, Chau CH, Price DK, et al. Precision Oncology Medicine: The Clinical Relevance of
Patient Specific Biomarkers Used to Optimize Cancer Treatment. J Clin Pharmacol 2016 doi:
10.1002/jcph.765 [published Online First: 2016/05/21]
47. Didelot X, Bowden R, Wilson DJ, et al. Transforming clinical microbiology with bacterial genome
sequencing. Nat Rev Genet 2012;13(9):601-12. doi: 10.1038/nrg3226 [published Online First:
2012/08/08]
48. Knoppers BM, Zawati MH, Senecal K. Return of genetic testing results in the era of whole-
genome sequencing. Nat Rev Genet 2015;16(9):553-9. doi: 10.1038/nrg3960 [published
Online First: 2015/08/05]
49. Roche MI, Berg JS. Incidental Findings with Genomic Testing: Implications for Genetic Counseling
Practice. Curr Genet Med Rep 2015;3(4):166-76. doi: 10.1007/s40142-015-0075-9 [published
Online First: 2015/11/14]
50. Swaminathan GJ, Bragin E, Chatzimichali EA, et al. DECIPHER: web-based, community resource
for clinical interpretation of rare variants in developmental disorders. Hum Mol Genet
2012;21(R1):R37-44. doi: 10.1093/hmg/dds362 [published Online First: 2012/09/11]
51. Bragin E, Chatzimichali EA, Wright CF, et al. DECIPHER: database for the interpretation of
phenotype-linked plausibly pathogenic sequence and copy-number variation. Nucleic Acids
Page 21 of 25
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review OnlyRes 2014;42(Database issue):D993-d1000. doi: 10.1093/nar/gkt937 [published Online First:
2013/10/24]
52. Philippakis AA, Azzariti DR, Beltran S, et al. The Matchmaker Exchange: a platform for rare
disease gene discovery. Hum Mutat 2015;36(10):915-21. doi: 10.1002/humu.22858
[published Online First: 2015/08/22]
53. Buske OJ, Schiettecatte F, Hutton B, et al. The Matchmaker Exchange API: automating patient
matching through the exchange of structured phenotypic and genotypic profiles. Hum Mutat
2015;36(10):922-7. doi: 10.1002/humu.22850 [published Online First: 2015/08/11]
54. Zemojtel T, Kohler S, Mackenroth L, et al. Effective diagnosis of genetic disease by computational
phenotype analysis of the disease-associated genome. Sci Transl Med 2014;6(252):252ra123.
doi: 10.1126/scitranslmed.3009262 [published Online First: 2014/09/05]
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Figure e: Current total families recruited to the Rare Disease arm of the Project, by disease category
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Figure f: Number of WGS returned to Genomics England from Illumina from the beginning of the Project
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Figure h: Number of overall and positive HPO terms per participant, for all participants in the rare disease arm of the programme with at least one HPO term entered
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Figure i: (a) Number of HES records by date for all current project participants. (b) Total HES records for all project participants, by source (log scale).
(c) Total records held for project participants, by external data set (log scale). (HES: Hospital Episode Statistics; DID: Diagnostic Imaging Dataset; PROMs: Patient Reported Outcome
Measures; ONS: Office for National Statistics)
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