Article | Published:

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

Nature volume 545, pages 446451 (25 May 2017) | Download Citation

  • A Corrigendum to this article was published on 20 December 2017

This article has been updated

Abstract

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

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Change history

  • 19 December 2017

    Please see accompanying Corrigendum (http://doi.org/nature25161). In the original Article, Figs 2a, 3a and b, Extended Data Figs 3d and 4c–f, Extended Data Table 2b, Supplementary Table 1 and parts of the text have been updated to include correct tumour volumetric and positron emission tomography data for 6 of 96 patients (CRUK0014, CRUK0030, CRUK0048, CRUK0059, CRUK0096 and CRUK0097) in the study. Correlation coefficients presented in the figures improve; levels of significance and conclusions remain unchanged. In addition, there were some formatting errors in the affiliations and corrected Source Data for Fig. 2 have been uploaded. The original Article has been corrected online.

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Acknowledgements

We acknowledge R. Macina for developing the collaboration between Natera and TRACERx. We thank S. Navarro and A. Tin for facilitating the PEACE ctDNA analysis. We thank the members of the TRACERx and PEACE consortia for participating in this study. C.S. is Royal Society Napier Research Professor. This work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169, FC001202), the UK Medical Research Council (FC001169, FC001202) and the Wellcome Trust (FC001169, FC001202). C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees Trust, NovoNordisk Foundation (ID 16584), the Prostate Cancer Foundation, the Breast Cancer Research Foundation and the European Research Council (THESEUS), and support was provided to C.S. by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre and the Cancer Research UK University College London Experimental Cancer Medicine Centre. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support towards the establishment of the Francis Crick Institute. The TRACERx study (https://clinicaltrials.gov/ct2/show/NCT01888601) is sponsored by University College London (UCL/12/0279) and has been approved by an independent Research Ethics Committee (13/LO/1546). TRACERx is funded by Cancer Research UK (grant number C11496/A17786) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre. The PEACE study (https://clinicaltrials.gov/ct2/show/NCT03004755) is sponsored by University College London (UCL/13/0165) and has been approved by an independent Research Ethics Committee (13/LO/0972). PEACE is funded by Cancer Research UK (C416/A21999) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre.

Author information

Author notes

    • Christopher Abbosh
    • , Nicolai J. Birkbak
    • , Gareth A. Wilson
    • , Mariam Jamal-Hanjani
    • , Tudor Constantin
    • , Raheleh Salari
    •  & John Le Quesne

    These authors contributed equally to this work.

Affiliations

  1. Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London WC1E 6DD, UK

    • Christopher Abbosh
    • , Nicolai J. Birkbak
    • , Gareth A. Wilson
    • , Mariam Jamal-Hanjani
    • , Selvaraju Veeriah
    • , Rachel Rosenthal
    • , Teresa Marafioti
    • , Thomas B. K. Watkins
    • , Nicholas McGranahan
    • , Sophia Ward
    • , Francisco Zambrana
    • , Diana Johnson
    • , Joanne Laycock
    • , Seema Shafi
    • , Justyna Czyzewska-Khan
    • , Crispin Hiley
    • , Siow Ming Lee
    • , Martin D. Forster
    • , Sam M. Janes
    • , Dahmane Oukrif
    • , Ayse U. Akarca
    • , Caroline Dive
    • , Charles Swanton
    • , Leticia Bosshard-Carter
    • , Gerald Goh
    • , Pat Gorman
    • , Nirupa Murugaesu
    • , Robert E. Hynds
    • , Kroopa Joshi
    • , Andrew Furness
    • , Assma Ben Aissa
    • , Yien Ning Sophia Wong
    •  & Andy Georgiou
  2. Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK

    • Nicolai J. Birkbak
    • , Gareth A. Wilson
    • , Thomas B. K. Watkins
    • , Nicholas McGranahan
    • , Sophia Ward
    • , Maise Al Bakir
    • , Eva Grönroos
    • , Andrew Rowan
    • , Tim Chambers
    • , Samra Turajlic
    • , Crispin Hiley
    • , Greg Elgar
    • , Charles Swanton
    • , Stuart Horswell
    • , Richard Mitter
    • , Mickael Escudero
    • , Hang Xu
    • , Jacki Goldman
    • , Richard Kevin Stone
    • , Tamara Denner
    • , Jennifer Biggs
    • , Marta Costa
    • , Sharmin Begum
    • , Ben Phillimore
    • , Emma Nye
    •  & Sofia Graca
  3. Natera Inc., 201 Industrial Road, San Carlos, California 94070, USA

    • Tudor Constantin
    • , Raheleh Salari
    • , Eser Kirkizlar
    • , Nicole Sponer
    • , Dina Hafez
    • , Ashwini Naik
    • , Apratim Ganguly
    • , Stephanie Kareht
    • , C. Jimmy Lin
    • , Matthew Rabinowitz
    •  & Bernhard G. Zimmermann
  4. Cancer Studies, University of Leicester, Leicester LE2 7LX, UK

    • John Le Quesne
    • , David A. Moore
    • , Luke Martinson
    • , Joan Riley
    • , Dean A. Fennell
    • , Jacqui A. Shaw
    • , Anne Thomas
    •  & Harriet Walter
  5. Department of Pathology, University College London Hospitals, 21 University Street, London WC1 6JJ, UK

    • Teresa Marafioti
    • , Mary Falzon
    • , Elaine Borg
    •  & Marco Novelli
  6. Advanced Sequencing Facility, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK

    • Sophia Ward
    • , Tim Chambers
    • , Nik Matthews
    • , Greg Elgar
    •  & Jennifer Biggs
  7. Department of Nuclear Medicine, University College London Hospitals, 235 Euston Road, Fitzrovia, London, NW1 2BU, UK

    • Francesco Fraioli
    •  & Raymondo Endozo
  8. Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    • Wenya Linda Bi
    • , Fiona M. Fennessy
    •  & Hugo J. W. L. Aerts
  9. Harvard Medical School, Boston, Massachusetts 02115, USA

    • Wenya Linda Bi
    • , Fiona M. Fennessy
    •  & Hugo J. W. L. Aerts
  10. Tumour Profiling Unit Genomics Facility, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK

    • Nik Matthews
  11. Renal and Skin Units, The Royal Marsden Hospital, London SW3 6JJ, UK

    • Samra Turajlic
  12. Department of Oncology, University College London Hospitals, 250 Euston Road, London NW1 2BU, UK

    • Siow Ming Lee
    • , Martin D. Forster
    • , Tanya Ahmad
    •  & Dionysis Papadatos-Pastos
  13. Department of Cardiothoracic Surgery, University College London Hospitals, 235 Euston Road, Fitzrovia, London NW1 2BU, UK

    • David Lawrence
    • , Martin Hayward
    • , Shyam Kolvekar
    •  & Nikolaos Panagiotopoulos
  14. Department of Respiratory Medicine, University College London Hospitals, 235 Euston Road, Fitzrovia, London NW1 2BU, UK

    • Sam M. Janes
    •  & Ricky Thakrar
  15. Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, Rayne Building, University College London, 5 University Street, London WC1E 6JF, UK

    • Sam M. Janes
    •  & Robert E. Hynds
  16. Department of Radiology, University College London Hospitals, 235 Euston Road, Fitzrovia, London NW1 2BU, UK

    • Asia Ahmed
  17. Institute of Cancer Studies, University of Manchester, Oxford Road, Manchester M13 9PL, UK

    • Fiona Blackhall
  18. The Christie Hospital, Manchester M20 4BX, UK

    • Fiona Blackhall
    •  & Yvonne Summers
  19. Department of Cardiothoracic Surgery, University Hospital South Manchester, Manchester M23 9LT, UK

    • Rajesh Shah
  20. Department of Pathology, University Hospital South Manchester, Manchester M23 9LT, UK

    • Leena Joseph
    •  & Anne Marie Quinn
  21. North West Lung Centre, University Hospital South Manchester, Manchester M23 9LT, UK

    • Phil A. Crosbie
  22. Department of Thoracic Surgery, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK

    • Babu Naidu
  23. Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK

    • Gary Middleton
  24. Department of Cellular Pathology, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK

    • Gerald Langman
    •  & Simon Trotter
  25. Department of Medical Oncology, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK

    • Marianne Nicolson
  26. Department of Cardiothoracic Surgery, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen AB25 2ZD, UK

    • Hardy Remmen
  27. Department of Pathology, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen AB25 2ZD, UK

    • Keith Kerr
  28. Department of Respiratory Medicine, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK

    • Mahendran Chetty
  29. Department of Radiology, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK

    • Lesley Gomersall
  30. Department of Thoracic Surgery, Glenfield Hospital, Leicester LE3 9QP, UK

    • Apostolos Nakas
    •  & Sridhar Rathinam
  31. Department of Radiotherapy, North Middlesex University Hospital, London N18 1QX, UK

    • Girija Anand
  32. Department of Respiratory Medicine, Royal Free Hospital, Pond Street, London NW3 2QG, UK

    • Sajid Khan
  33. Department of Respiratory Medicine, Barnet and Chase Farm Hospitals, Wellhouse Lane, Barnet EN5 3DJ, UK

    • Sajid Khan
  34. Department of Respiratory Medicine, The Princess Alexandra Hospital, Hamstel Road, Harlow CM20 1QX, UK

    • Peter Russell
  35. Department of Clinical Oncology, St.Luke’s Cancer Centre, Royal Surrey County Hospital, Guildford GU2 7XX, UK

    • Veni Ezhil
  36. Department of Pathology, Ashford and St. Peter’s Hospital, Guildford Road, Chertsey, Surrey KT16 0PZ, UK

    • Babikir Ismail
  37. Department of Respiratory Medicine, Ashford and St. Peter’s Hospital, Guildford Road, Chertsey, Surrey KT16 0PZ, UK

    • Melanie Irvin-Sellers
  38. Department of Radiology, Ashford and St. Peter’s Hospital, Guildford Road, Chertsey, Surrey KT16 0PZ, UK

    • Vineet Prakash
  39. Department of Clinical Oncology, Velindre Hospital, Cardiff CF14 2TL, UK

    • Jason F. Lester
  40. Department of Cardiothoracic Surgery, University Hospital of Wales, Cardiff CF14 4XW, UK

    • Malgorzata Kornaszewska
  41. Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Heath Park, Cardiff, UK

    • Richard Attanoos
  42. Department of Radiology, University Hospital Llandough, Cardiff CF64 2XX, UK

    • Haydn Adams
  43. Department of Respiratory Medicine, University Hospital Llandough, Cardiff CF64 2XX, UK

    • Helen Davies
  44. University College London Experimental Cancer Medicine Centre GCLP Facility, University College London Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London WC1E 6DD, UK

    • John A. Hartley
    •  & Helen L. Lowe
  45. Department of Respiratory Medicine, The Whittington Hospital NHS Trust, London, N19 5NF, UK

    • Sara Lock
    •  & Azmina Verjee
  46. University College London, Cancer Research UK and UCL Cancer Trials Centre, London W1T 4TJ, UK

    • Natasha Iles
    • , Harriet Bell
    • , Yenting Ngai
    • , Allan Hackshaw
    • , Sean Smith
    •  & Nicole Gower
  47. Centre for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark

    • Zoltan Szallasi
  48. Computational Health Informatics Program (CHIP), Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

    • Zoltan Szallasi
  49. MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, 1091 Budapest, Hungary

    • Zoltan Szallasi
  50. Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany

    • Roland F. Schwarz
  51. Bill Lyons Informatics Centre, University College London Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London WC1E 6DD, UK

    • Javier Herrero
  52. Department of Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK

    • Aengus Stewart
  53. Cancer Immunology Unit, University College London Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London WC1E 6DD, UK

    • Sergio A. Quezada
    •  & Karl S. Peggs
  54. Cancer Genomics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK

    • Peter Van Loo
  55. Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium

    • Peter Van Loo
  56. Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK

    • Caroline Dive
    • , Jonathan Tugwood
    • , Ged Brady
    • , Dominic G. Rothwell
    • , Francesca Chemi
    • , Jackie Pierce
    •  & Sakshi Gulati
  57. Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215-5450, USA

    • Hugo J. W. L. Aerts
  58. Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK

    • Babu Naidu
  59. University College London Hospitals NHS Foundation Trust, London, UK

    • Celia Simeon
    • , Gemma Hector
    • , Amy Smith
    • , Marie Aranda
    • , Dawn Carnell
    • , Ruheena Mendes
    • , Jeremy George
    • , Neal Navani
    • , Magali Taylor
    •  & Junaid Choudhary
  60. University Hospital South Manchester, Manchester, M23 9LT, UK

    • Raffaele Califano
    • , Paul Taylor
    • , Piotr Krysiak
    • , Kendadai Rammohan
    • , Eustace Fontaine
    • , Richard Booton
    • , Matthew Evison
    • , Stuart Moss
    • , Faiza Idries
    • , Paul Bishop
    • , Anshuman Chaturvedi
    • , Helen Doran
    •  & Elaine Smith
  61. Manchester Cancer Research Centre Biobank, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK

    • Angela Leek
    • , Phil Harrison
    • , Katrina Moore
    • , Rachael Waddington
    • , Juliette Novasio
    •  & Jane Rogan
  62. Heart of England NHS Foundation Trust, Birmingham, UK

    • Mary Bellamy
    • , Hollie Bancroft
    • , Amy Kerr
    • , Salma Kadiri
    • , Joanne Webb
    •  & Madava Djearaman
  63. NIHR Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK

    • William Monteiro
    •  & Hilary Marshall
  64. University Hospitals of Leicester NHS Trust, Leicester, UK

    • Louise Nelson
    • , Jonathan Bennett
    •  & Lindsay Primrose
  65. Barnet and Chase Farm Hospitals, Wellhouse Lane, Barnet EN5 3DJ, UK

    • Anita Amadi
  66. Aberdeen Royal Infirmary, Aberdeen, AB25 2ZN, UK

    • Shirley Palmer
    • , Joy Miller
    •  & Keith Buchan
  67. Clinical Trials Unit, Velindre Cancer Centre, Whitchurch, Cardiff, CF14 2TL, UK

    • Alison Edwards
  68. Cardiff & Vale University Health Board, Cardiff, UK

    • Fiona Morgan
    •  & Helen Davies
  69. Independent Cancer Patients’ Voice, 17 Woodbridge Street, London, EC1R 0LL, UK

    • Mairead MacKenzie
    •  & Maggie Wilcox
  70. University of Southampton and Southampton University Hospitals, Southampton, UK

    • Christian Ottensmeier
    • , Serena Chee
    • , Benjamin Johnson
    • , Aiman Alzetani
    •  & Emily Shaw
  71. Royal Brompton and Harefield NHS Foundation Trust, London, UK

    • Eric Lim
    • , Paulo De Sousa
    • , Monica Tavares Barbosa
    • , Alex Bowman
    • , Simon Jordan
    • , Alexandra Rice
    • , Hilgardt Raubenheimer
    • , Chiara Proli
    • , Maria Elena Cufari
    • , John Carlo Ronquillo
    • , Angela Kwayie
    • , Harshil Bhayani
    • , Morag Hamilton
    • , Yusura Bakar
    • , Natalie Mensah
    • , Lyn Ambrose
    • , Anand Devaraj
    • , Silviu Buderi
    • , Jonathan Finch
    • , Leire Azcarate
    • , Hema Chavan
    • , Sophie Green
    • , Hillaria Mashinga
    •  & Andrew G. Nicholson
  72. National Heart and Lung Institute, Imperial College, Sydney Street, London, UK

    • Andrew G. Nicholson
  73. Barts Health NHS Trust, London, UK

    • Kelvin Lau
    • , Michael Sheaff
    • , Peter Schmid
    •  & John Conibear
  74. The Princess Alexandra Hospital NHS Trust, Harlow, UK

    • Teresa Light
    •  & Tracey Horey
  75. Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

    • Sarah Danson
    • , Jonathan Bury
    • , John Edwards
    • , Jennifer Hill
    • , Sue Matthews
    • , Yota Kitsanta
    • , Kim Suvarna
    • , Patricia Fisher
    •  & Allah Dino Keerio
  76. Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, UK

    • Michael Shackcloth
    • , John Gosney
    • , Pieter Postmus
    • , Sarah Feeney
    •  & Julius Asante-Siaw
  77. Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK

    • Stefan Dentro
  78. Bioinformatics Group, Department of Computer Science, University College London, UK

    • Christophe Dessimoz
  79. University of Lausanne, 1015 Lausanne, Switzerland

    • Christophe Dessimoz
  80. SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland

    • Christophe Dessimoz
  81. Research Department of Haematology, University College Cancer Institute, London WC1E 6DD, UK

    • Karl S. Peggs

Consortia

  1. The TRACERx consortium

  2. The PEACE consortium

    A list of participants and their affiliations appears in the Supplementary Information.

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Contributions

C.A., N.J.B., G.A.W., M.J.-H., T.C., R.Sa. and J.L.Q. contributed equally to this work. D.A.M. and S.V. contributed equally to this work as joint second authors. C.A. and C.S. co-wrote the manuscript. C.A., M.J.-H. and C.S. conceived the study design. C.A., N.J.B., G.A.W. and R.R. integrated clinicopathological data, exome data and ctDNA data. M.R., B.G.Z., C.J.L., T.C., R.S., E.K., N.S., D.H., A.Nai. and A.G. conducted and analysed multiplex-PCR NGS experimental work for ctDNA data. N.J.B., G.A.W., T.B.K.W., M.A.B., R.R. and N.M. conducted M-seq analyses of exome data. J.L.Q., T.M. and D.A.M. conducted the pathological review. F.F., R.E. and F.Z. conducted radiological review of PET scans. H.J.W.L.A., W.L.B., F.M.F. and N.J.B. conducted radiomic analyses. S.V., D.J., J.L., S.S., J.C.-K., A.R., T.C., D.O. and A.U.A. conducted TRACERx sample processing. G.E., S.W., N.M. and G.A.W. conducted exome sequencing. L.M., J.R. and J.A.S. conducted ctDNA cross-platform validation. M.J.-H., C.D., J.A.S. and C.S. designed the study protocols. C.H., S.M.L., M.D.F., T.A., M.F., E.B., D.L., M.H., S.Ko., N.P., S.M.J., R.T., A.A., F.B., Y.S., R.Sh., L.J., A.M.Q., P.A.C., B.N., G.M., G.L., S.T., M.N., H.R., K.K., M.C., L.G., D.A.F., A.Nak., S.R., G.A., S.Kh., P.R., V.E., B.I., M.I.-S., V.P., J.F.L., M.K., R.A., H.A., H.D. and S.L. are clinical members of TRACERx study sites. J.A.H. and H.L.L. run the UCL GCLP facility. A.H., H.B., N.I. and Y.N. were involved in study oversight. J.A.S., J.L.Q., Z.S., E.G., S.Ka., S.T., M.A.B., R.F.S., J.H., A.S., S.A.Q., P.V.L., C.D., C.J.L. and B.G.Z. gave advice and reviewed the manuscript. A.H. gave statistical advice. C.S. provided overall study oversight.

Competing interests

T.C., R.S., E.K., N.S., D.H., A.Nai., A.G., S.Ka., J.L., B.G.Z. and M.R. are all employees or former employees of Natera Inc. and own stock and/or options to purchase stock. C.A., M.J.-H., G.W., C.S. and Natera Inc. employees are co-inventors of or contributors to unpublished patent applications based on the work in this manuscript, filed by UCL Business Plc and Natera Inc. C.S. has had the following financial relationships in the last 36 months: Boehringer Ingelheim, consulting and speaker fees; Novartis, consulting and speaker fees; Eli Lilly, speaker fees; Roche, consulting and speaker fees; GlaxoSmithKline, speaker fees; Pfizer, speaker fees; Celgene, speaker fees; Servier, speaker fees; Grail, scientific advisory board and stock options; APOGEN Biotechnologies, scientific advisory board and stock options; EPIC Biosciences, scientific advisory board and stock options; Achilles Therapeutics, founder and stock options. In 2015 C.S. was a member of a Natera advisory board and received an honorarium.

Corresponding author

Correspondence to Charles Swanton.

Reviewer Information Nature thanks S. Lippman, R. Rosell and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

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    Supplementary Information

    This file contains the full list of authors and affiliations for the PEACE Consortium.

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https://doi.org/10.1038/nature22364

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