Next Steps in the Sequence
Total Page:16
File Type:pdf, Size:1020Kb
Next steps in the sequence The implications of whole genome sequencing for health in the UK PHG Foundation project team and authors Dr Caroline Wright* Programme Associate Dr Hilary Burton Director Ms Alison Hall Project Manager (Law) Dr Sowmiya Moorthie Project Coordinator Dr Anna Pokorska-Bocci‡ Project Coordinator Dr Gurdeep Sagoo Epidemiologist Dr Simon Sanderson Associate Dr Rosalind Skinner Senior Fellow ‡ Corresponding author: [email protected] * Lead author Disclaimer This report is accurate as of September 2011, but readers should be aware that genome sequencing technology and applications will continue to develop rapidly from this point. This report is available from www.phgfoundation.org Published by PHG Foundation 2 Worts Causeway Cambridge CB1 8RN UK Tel: +44 (0)1223 740200 Fax: +44 (0)1223 740892 October 2011 © 2011 PHG Foundation ISBN 978-1-907198-08-3 Cover photo: http://www.sxc.hu/photo/914335 The PHG Foundation is the working name of the Foundation for Genomics and Population Health, a charitable organisation (registered in England and Wales, charity no. 1118664; company no. 5823194) which works with partners to achieve better health through the responsible and evidence-based application of biomedical science. Acknowledgements Dr Tom Dent contributed the section on risk prediction in the Other Applications chapter. Dr Richard Fordham contributed to the Health Economics chapter. Professor Anneke Lucassen, Dr Kathleen Liddell and Professor Jenny Hewison contributed to the Ethical, Legal and Social Implications chapter. Dr Ron Zimmern contributed to the Policy Analysis and Recommendations chapters. The PHG Foundation is grateful for the expert guidance and advice provided by the external Steering Group, in particular to Dr Jo Whittaker, Mr Chris Mattocks and Dr Paul Flicek for their extensive comments on the manuscript. The project team would also like to thank Dr Sarah Wordsworth for her initial advice on the health economics content, and all the participants of the two invited expert workshops (see Appendices), whose valuable contributions helped shape the recommendations within this report. Funding This project was funded by the PHG Foundation, with additional financial support from Illumina. The second expert workshop for the project was supported by the University of Cambridge Centre for Science and Policy (CSaP) and the Wellcome Trust. The contributions of these supporters are gratefully acknowledged. Contents Executive summary ....................................................................3 Glossary of acronyms ..................................................................7 Glossary of genetic terms ............................................................9 1 Introduction .................................................................... 11 2 The human genome .......................................................... 13 3 DNA sequencing technologies ............................................. 19 4 Informatics ..................................................................... 33 5 Applications in inherited and heritable diseases ....................... 45 6 Applications in cancer ....................................................... 59 7 Other potential applications ................................................ 75 8 Ethical, legal and social implications ..................................... 85 9 Health economics ............................................................109 10 Laboratory service delivery models ......................................123 11 Analysis and policy development ........................................141 12 Policy recommendations ....................................................153 13 References ....................................................................161 14 Appendices ....................................................................181 Next steps in the sequence 2 The implications of whole genome sequencing for health in the UK Executive summary Context and process The rapid development of new high-throughput and massively parallel DNA sequencing technologies has substantially reduced both the cost and the time required to sequence an entire human genome. It may soon be easier and cheaper to sequence an entire genome than to sequence a single gene or genotype a series of known mutations. Whole genome sequencing, together with our evolving knowledge of genes and disease, is likely to change the current practice of medicine and public health by facilitating more accurate, sophisticated and cost-effective genetic testing. The development of genomic medicine was considered in a House of Lords Report in 2009, which identified the need for a strategic vision for implementation of genomic technologies within the National Health Service (NHS) to maximise both their health and cost benefits.The PHG Foundation – an organisation dedicated to the evaluation of genome-based technologies for the benefit of health and healthcare – formulated a response to that report, and has subsequently undertaken a year-long project to evaluate the implications of whole genome sequencing for health services and develop recommendations that will facilitate its adoption into the NHS to improve patient care. During the preparation of this report, the authors were guided by the following key questions: a) What is the role of new DNA sequencing technologies in medicine and population health, in the short to medium term, and how will they alter or augment routine clinical practice? b) What new ethical, legal, social and economic issues are raised by whole genome sequencing? c) What are the implications of whole genome sequencing for diagnostic services within the UK and health services more generally? d) What operational barriers exist to adoption within health services and how should they be tackled? In this report, we have brought together a diverse range of relevant information and stakeholder opinions to produce a comprehensive overview of the clinical impact of sequencing whole human genomes in the short to medium term. Although the scope of this project is large, we believe that it is crucial to consider the numerous different aspects together in order to make informed recommendations about the possible implementation of such a wide-ranging and potentially disruptive technology. To the best of our knowledge, no other group has produced such a comprehensive overview of the status quo and subsequently developed realistic future scenarios for medical human genome sequencing. The first ten chapters of this report present background research undertaken throughout 2010-11 by the PHG Foundation and supervised by an expert steering group. The chapters cover a broad range of topics relevant to the implementation of whole genome sequencing: 1) Project methodology and terms of reference 2) Introduction to the human genome 3) DNA sequencing technologies 4) Informatics and analysis 5) Applications of whole genome sequencing in inherited and heritable diseases 6) Applications of whole genome sequencing in cancer 7) Other health applications (specifically risk prediction, pharmacogenetics and tissue typing) 8) Ethical, legal and social issues 9) Health economics 10) Laboratory service delivery models 3 Next steps in the sequence The final two chapters present an analysis of discussions at two invited stakeholder workshops, held in March and June 2011, in which we developed scenarios and recommendations for implementation of whole genome sequencing within the UK. Summary of key findings Whole genome sequencing (WGS) has novel implications beyond traditional genetic testing because of the sheer volume and complexity of data generated. Each individual genome contains around 3-4 million variants that are not present in the reference human genome sequence. Only a small number of these variants will have important clinical consequences, and although some may also have implications for family relatedness, the vast majority will be of uncertain or no clinical or personal significance. In addition, cancer genomes have numerous additional somatic alterations superimposed on the patient’s inherited genome. These acquired changes constitute the ‘genetic fingerprint’ of each cancer type in an individual patient, but again, only a small number will be clinically significant. Understanding the health impact of individual genomic variants presents a considerable challenge for analysis, interpretation and management of the data. Although most WGS to date has been carried out in a research setting (or through consumer genomics companies), here we focus specifically on service delivery within the NHS for the purpose of improving patient diagnosis, clinical outcomes or disease prevention. In this scenario, it is useful to make a distinction between an assay (sequencing an individual’s genome) and a test (analysing any portion of that genome sequence for a specific purpose).The former contains no medical information per se, but is essentially a translation of the genetic code from DNA into a string of data stored on a computer; next generation sequencing (NGS) technologies have radically reduced both the cost and time required to accomplish this process. In contrast, the latter is an interpretive step which requires purposeful analysis of the genome sequence, directed by clinical symptoms/phenotypes or disease risk and informed by prior knowledge of the likely pathogenicity of genomic variants. Although the cost and time to sequence a human genome has decreased dramatically,