What is genomics: Techniques and costs
Genomics is a genetic discipline concerned with mapping, analysing, modifying and interrogating the whole genome of an organism. It considers the entire set of genes and their functions within their structural landscape and surrounding non-coding sequences. Given the large size of genomes, genomics is frequently concerned with broad questions and uses large datasets and statistical methods to find patterns and come to high-level conclusions. However, it also examines and compares single individual genomes to identify differences and rare events. Functional genomics in turn looks at the function of genes in different contexts and tries to integrate datasets such as DNA sequence (genome), DNA methylation (methylome), gene transcription (transcriptome) and protein expression (proteome) to understand cellular or tissue function.
The field of genomics has witnessed an explosion in interest in the last ten years due to the rapid advances in sequencing technologies. Generating the data is no longer a limitation; it is fast and becoming cheaper day by day. From 2008, with the introduction of next generation sequencing (NGS), the cost of re-sequencing of a human-size genome dropped from $1 million to $1000 according to NIH monitoring figures.1 Costs including laboratory activity to produce the sequence have been driven down by the intense competition between sequencing technology companies, to the great benefit of the wider scientific community.2 Bioinformatic algorithms concerned with the alignment, mapping and filtering sequencing data as well as variant calling and variant annotation have advanced rapidly to accommodate this dramatic increase in activity. As a result, both commercial and public bioinformatic pipelines have become highly sophisticated and capable of producing high-quality, reliable data. Of particular relevance to the study of genetic variation, although manufacturers provide pre-made tools for the analysis of VCF files (variant call format, a file containing the variations against a reference sequence), custom scripts are often favoured in order to tailor pipelines to the specific analytical or clinical requirement. However, interpretation of such data with regards to their clinical significance is lagging behind and will require systematic efforts to help it advance.
Clinical applications of genomics: promises and risks
Translational research has seen application of genomics in an increasing number of clinical fields, from the diagnosis or monitoring of disease to the development, choice or stratification of therapies. However, translating the use of genomics into the clinic is a daunting business because of the wide uncertainties implicit to large and complex datasets. Constitutional genetics is already benefiting from whole genome (WGS) or whole exome sequencing (WES). With the possibility to interrogate the genome of an individual on a large scale has come the immense hope for the end of the diagnostic odyssey for people or families with rare genetic disorders. But while the possibilities are immense, the risks are also great: What will be the implication for the patient and their family if we see something we didn’t look for, so-called ‘incidental findings’? How will the patients and their doctors deal with uncertainty when there is no clear-cut answer? A genetic result can help the choice of therapy, but it can equally generate concern and anxiety. These are highly pertinent questions that render the task of translating genomic data into clinical advice complex and sensitive.3 The ultimate goal of genomic data interpretation in rare disease diagnosis is to spot the critical difference, or find the rare event in the whole of the genome that is sufficiently deleterious to cause disease.
As with inherited diseases, genomics has become an important tool for the diagnosis and management of acquired disorders. Large international efforts such as the Cancer Genome Atlas, for example (TCGA4), have led to the identification of recurrent somatic mutations that drive oncogenesis in a wide variety of cancers, through the comparative sequencing of cancer and constitutional genomes.5 These advances have truly revolutionised both the understanding of the molecular pathogenesis of cancer as well as cancer diagnosis, classification and monitoring.
Another important area of progress is targeted cancer therapy and pharmacogenomics, which are already in use as personalised medicine tools. Amongst the most used are HER2 in breast cancer (trastuzumab), KRAS/NRAS in colorectal cancer (cetuximab and panitumumab), EGFR and ALK in non-small cell lung cancer (gefitinib/erlotinib and crizotinib), BRAF in melanoma (vemurafenib) and chronic myelogenous leukaemia (imatinib). So far, approximately 50 targeted drugs have acquired regulatory approval to treat nearly three dozen types of solid tumours and haematological malignancies (www.centerwatch.com/drug-information/fda-approved-drugs). Many of the targeted therapies are approved along with a specific molecular test or companion diagnostic kit, making the precision molecular diagnostics a mandatory prerequisite for the cost-effective use of targeted treatment. With the wider availability of tumour sequencing, more of these tests, or combinations thereof, could be developed to improve and personalise treatment further. However, although screening and diagnostic tests are already possible, the pharmacogenomics field is complicated due to high complexity of the cancer genomes and the average ten-year period for drug development. A recent report by Mody et al (2015) describe the clinical utility of combined germline exome sequencing with DNA and RNA sequencing of tumour in paediatric cases. The study set out to identify actionable germline mutations and somatic mutations that may modulate the histopathology diagnosis and be amenable to specific drugs. The study reports 46% of cases with actionable results, half of those translating into a change of management including therapy. The authors stress that unfortunately targeted therapy was often unavailable. Commenting on this study, Schnepp et al (2015) highlight the importance of the multidisciplinary board for the interpretation of the data but also reflects on practicality and best use of cancer genomics:
“Although comprehensive sequencing is clearly optimal for discovery efforts, gene panel NGS strategies that provide robust depth of coverage (necessary to detect potentially important subclonal events) and that can now be manufactured to cover the majority of known gene-fusion events have significant advantages as a companion diagnostic when the goal of the assay is to promptly assign therapy because results generally can be returned in less than 2 weeks. There is clearly no single best technology, and the field will likely adapt a hybrid approach to address practical, clinical, and financial pressures.”
The integration of genomics in cancer diagnosis practice is therefore still underway and may involve a phased adaptation to technology first – transferring all molecular testing to gene panels and NGS sequencing – and then the introduction of blood/tumour WGS when interpretation is deemed feasible.
The third main area of genomics in medicine concerns microbiology and virology and their role in infectious diseases diagnostics and public health surveillance. Sequencing of pathogen genomes can be used to discriminate between species with high confidence, while informing about features such as virulence, resistance and phylogeny. Pathogen sequence information can therefore be used for rapid diagnosis and treatment and transfusion safety, as well as monitoring data for outbreak protection and guideline for drug uses. The recent national strategic review by the PHG Foundation enounced important recommendations for the implementation of ‘pathogen genomics’.8 The report discusses how current practice is limited to outbreak detection and control, for example reporting of a MRSA outbreak within the neonatal unit at Addenbrooke’s Hospital.9 The PHG Foundation proposes a framework for the development of integrated and nationally coordinated diagnostic pathogen genomics based on the concerted development of a strategic capacity and integration of knowledge and data. As in rare diseases, genomics of infectious diseases has the potential to halt the diagnostic odyssey, with the added complexity of obligatory rapid turnaround. Integrated testing is being developed on a research basis, for example the UCSF’s precision medicine test for infection,10 using a microarray and massively parallel deep sequencing approach to comprehensively identify infectious agents in blood. Therefore with its resolution power combined with capacity to improve the laboratory workflow, pathogen genomics is a very promising innovation in the diagnostic and management of infectious disease.
Genomics in the UK NHS
Large projects, such as the 100,000 Genomes Project led by Genomics England and in partnership with sequencing industries, lead the way. In the UK, the structural organisation into genomic medicine centres will play a critical role in the future to channel results and ensure the legacy of the 100,000 Genomes Project. Focusing on rare diseases, cancer and infectious diseases, the project embraces the three main branches of genomics as described above. The proposed infrastructure will bring together clinicians, diagnostic laboratories and research units into ‘clinical interpretation partnerships’, therefore building bridges across disciplines and accelerating translational research into clinical utility. Genomics England says:
“For patients with rare diseases, we hope to help with diagnoses, for cancer patients we hope the programme will help to target medicines more appropriately and for infectious diseases it may help to generate new opportunities for therapies for these diseases”.
Translational genomics research is, of course, not restricted to the Genomics England initiative and many applications of genomics are being developed in partnership with industry.
Genomics thus carries huge opportunities to improve clinical practice in many fields across pathology. Quicker, cheaper, more practical and more easily integrated practice, genomics will drive improvement in patient pathways. As the invention of the x-ray at the end of the 19th century drove a revolution in medical imaging,11 rapidly improving technological advances are driving the field of genomics. Harnessing the novel opportunities brought by genomics while maintaining patient safety and integrating novel ways within traditional pathology is a major challenge that the NHS must approach. Training the current workforce and educating future ones across scientific, medical and other healthcare professional disciplines seems like a gargantuan task. However, a combination of policy, education and training programmes is shaping the current top-down approach to change.
Challenges to the current workforce
The bottleneck to genomics approaches is no longer technical; it resides in the interpretation of data. It is not easy and remains very time consuming. The main challenge for the current workforce is that somehow we first have to ‘unlearn’ in order to learn new ways. From a rare disease point of view, screening a gene will result in a ‘yes’ or ‘no’ answer within the limit of the given analysis, whereas the interpretation of a whole genome is based on the relative frequency of an event compared to control populations and in the context of a specific disease. This requires appropriate filtering of data and balanced judgement using multi-source information.
This heuristic approach contrasts sharply with the more or less binary evaluation that prevails in traditional genetic testing. Fear for the increase of uncertainty and the decrease in quality fuel resistance to change. Somehow we have to reframe our expectations. Partly, this may be a matter of solving the ‘excellent being the enemy of the good’ and moving through the shift in paradigm that will drive the democratisation of genomics.12 Genetic testing will not just be required within a genetics clinics, but will be integral to any clinic where a genetic aetiology of the disease is suspected.13,14 This is already happening, and it can disturb the social order and lead to confusion by blurring boundaries. Building bridges across disciplines will enable the current genetics workforce, pathologists in general and other medical disciplines to embrace genomics and make the most of it for the great benefit of our patients. Moreover, the risk of misdiagnosis and uncertainty can be greatly reduced by the setting of rigorous quality measures of the raw data and processes of interpretation using evidence-based sources and scientific expertise15.
Genomics transformation: policy, education and training
The 5 Year Forward View for the NHS (2014)16 identifies technological advances and its ability to transform the way we predict, diagnose and treat disease as a fundamental challenge for the health system. Accelerating useful health innovation via translational research to promote advances in the diagnostic setting is a top priority. In that respect, the 100,000 Genomes Project is a major flagship project for the NHS. The Accelerated Access Review17 discusses further factors that have been impeding translation of innovation in clinical practice, especially in the precision medicine field, one of the key applications of genomics. Supporting a modern workforce in collaboration with Health Education England (HEE) is recognised in the 5 Year Forward View as a necessity to bring about new care models, innovation and working across boundaries. In a report commissioned by the Office of Life Science,18 shortage of skills in bioinformatics and genomics is recognised as a key constraint for the evolution of the sector, the major challenge being data analysis and interpretation.
The HEE framework 15 (2014–2029)19 places emphasis on genomics as a driver for innovation and recognises the need to invest in appropriate training of both existing and future workforce to ensure the legacy of the 100,000 Genomes Project and the successful integration of genomics into mainstream care pathways. With this in mind, £25 million has been allocated to support genomics education and the workforce transformation project. The objective of the transformation project is to educate the entire healthcare workforce, including commissioners and GPs. The HEE transformation programme includes training across a large proportion of the workforce via targeted programmes and the recruitment of new cohorts of scientists in new disciplines that will support the development of genomics in practice. The ultimate goal is to create an intersection of skills for better working across boundaries between clinical scientists, pathologists, clinicians, industry and academia. A comprehensive program of education includes:
• the commissioning of new scientist training programmes (STP) in molecular pathology, genomics and genetic counselling and bioinformatics. The National School of Healthcare Science, part of HEE since 2013, provides the structure for the STP training
• HEE-sponsored higher specialist scientist training (HSST) posts have been filled in genetics and molecular pathology, in order to produce consultant clinical scientists in these areas
• the introduction of a sponsored MSc in genomic medicine offered by several universities and available to current staff on a part-time basis, including the option to subscribe to individual modules as CPD units. In addition, online courses and resources are offered on the Genomics education website20
• the encouragement of translational research stemming from the 100,000 Genomes Project via research fellowships for PhD students and post-doctoral scientists
• raising the awareness of genomic medicine by non-specialist staff.
This College has a major role to play in training. An approved curriculum is now available in molecular pathology and examinations leading to Fellowship are in development. The first Part 1 examination will have taken place by the time this article is published. Successful completion of the curriculum is an integral component of the five-year HSST programme. A HSST clinical bioinformatics curriculum is under development.
Regulation and monitoring of outcomes are overseen by the Association of Clinical Scientists and the Academy for Healthcare Science, both providing standards and regulations for the recommendation of trainees to the Health and Care Professions Council (HCPC).
In parallel to the scientific workforce transformation, the integration of genomics into clinical practice will also require evolution of medical training. Aspects of this are covered in the article elsewhere in this issue by Dr Young.
The genomics movement
In addition to generating policy and new education programmes, the genomics movement will need enthusiasts and tempered radicals to ensure continuity and commitment to the organisational change required to fully integrate genomics into practice. Clinical geneticists organising their own future as interpreters and researchers highlights the need to break boundaries between the medical and scientific workforce. As the emphasis of our role turns towards the analysis of large datasets, increased joined practice and co-leadership with pathologists, medical geneticists, scientists and other specialties are necessary to make clinical interpretations while developing safe practices and monitoring outcomes.15 The concept of the multidisciplinary team (MDT) as a cross-boundary vehicle for progress needs to shift to the centre of a new work organisation3 and inevitably MDT collaboration and distributed leadership will emerge as the new ethical values in medicine.21 Innovative thinking will come from the establishment of novel relationships across traditional boundaries.22 In turn, we will become more versatile in our intellectual aptitude to integrate information and stimulate new critical thinking.
Building this strategic capacity will enhance our ability to play an important role in designing the practical delivery of genomics in the clinic. The supporting structures of the nascent Genomic Medicine Centres (GMCs) and their parent, Genomics England, have been founded to nurture the genomics transformation. GMCs provide the opportunity to change the organisational landscape and build a new collective identity amongst healthcare professionals. Being part of the foundation of the genomics movement enables participants to drive policy in that area, activity that has always been an integral role of healthcare scientists.23 In addition to the clinical utility of WGS, the study of practicality and cost-effectiveness for laboratory routine and patient pathways is a topic that will necessarily drive changes in policy at high level. Organisational change is a critical step for the genomics transformation, although the relationship between ‘biotech revolution’ and policy-making needs is not always obvious and needs caution.24 The genomics transformation is a large-scale change for medicine, entailing a relatively quick shake-up of culture and values in GMCs in order to sustain the growing demands and make the most of the possibilities.
Genomics is the story of us and the story of now. Investment in training will certainly help promote new values but professionals must also drive the movement from within.
Dr Isabelle Delon
Clinical Scientist in Molecular Genetics (HSST trainee)
Cambridge University Hospitals NHS Foundation Trust
Dr Mike Scott
Haematopathology and Oncology Diagnostic Service
Cambridge University Hospitals NHS Foundation Trust
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