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Nature. 2017 Apr 26;545(7655):446-451. doi: 10.1038/nature22364.

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

Collaborators (227)

Swanton C, Jamal-Hanjani M, Abbosh C, Veeriah S, Shafi S, Czyzewska-Khan J, Johnson D, Laycock J, Bosshard-Carter L, Goh G, Rosenthal R, Gorman P, Murugaesu N, Hynds RE, Wilson GA, Birkbak NJ, Watkins TBK, McGranahan N, Horswell S, Bakir MA, Grönroos E, Mitter R, Escudero M, Stewart A, Van Loo P, Rowan A, Xu H, Turajlic S, Hiley C, Goldman J, Stone RK, Denner T, Matthews N, Elgar G, Ward S, Biggs J, Costa M, Begum S, Phillimore B, Chambers T, Nye E, Graca S, Joshi K, Furness A, Ben Aissa A, Wong YNS, Georgiou A, Quezada SA, Peggs KS, Hartley JA, Lowe HL, Herrero J, Lawrence D, Hayward M, Panagiotopoulos N, Kolvekar S, Falzon M, Borg E, Marafioti T, Simeon C, Hector G, Smith A, Aranda M, Novelli M, Oukrif D, Akarca AU, Janes SM, Thakrar R, Forster MD, Ahmad T, Lee SM, Papadatos-Pastos D, Carnell D, Mendes R, George J, Navani N, Ahmed A, Taylor M, Choudhary J, Summers Y, Califano R, Taylor P, Shah R, Krysiak P, Rammohan K, Fontaine E, Booton R, Evison M, Crosbie PA, Moss S, Idries F, Joseph L, Bishop P, Chaturvedi A, Quinn AM, Doran H, Leek A, Harrison P, Moore K, Waddington R, Novasio J, Blackhall F, Rogan J, Smith E, Dive C, Tugwood J, Brady G, Rothwell DG, Chemi F, Pierce J, Gulati S, Naidu B, Langman G, Trotter S, Bellamy M, Bancroft H, Kerr A, Kadiri S, Webb J, Middleton G, Djearaman M, Fennell DA, Shaw JA, Quesne JL, Moore DA, Thomas A, Walter H, Riley J, Martinson L, Nakas A, Rathinam S, Monteiro W, Marshall H, Nelson L, Bennett J, Primrose L, Anand G, Khan S, Amadi A, Nicolson M, Kerr K, Palmer S, Remmen H, Miller J, Buchan K, Chetty M, Gomersall L, Lester JF, Edwards A, Morgan F, Adams H, Davies H, Kornaszewska M, Attanoos R, Lock S, Verjee A, MacKenzie M, Wilcox M, Bell H, Iles N, Hackshaw A, Ngai Y, Smith S, Gower N, Ottensmeier C, Chee S, Johnson B, Alzetani A, Shaw E, Lim E, De Sousa P, Barbosa MT, Bowman A, Jordan S, Rice A, Raubenheimer H, Proli C, Cufari ME, Ronquillo JC, Kwayie A, Bhayani H, Hamilton M, Bakar Y, Mensah N, Ambrose L, Devaraj A, Buderi S, Finch J, Azcarate L, Chavan H, Green S, Mashinga H, Nicholson AG, Lau K, Sheaff M, Schmid P, Conibear J, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Russell P, Light T, Horey T, Danson S, Bury J, Edwards J, Hill J, Matthews S, Kitsanta Y, Suvarna K, Fisher P, Keerio AD, Shackcloth M, Gosney J, Postmus P, Feeney S, Asante-Siaw J, Constantin T, Salari R, Sponer N, Naik A, Zimmermann BG, Rabinowitz M, Aerts HJWL, Dentro S, Dessimoz C.

Author information

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.
2
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
3
Natera Inc., 201 Industrial Road, San Carlos, California 94070, USA.
4
Cancer Studies, University of Leicester, Leicester LE2 7LX, UK.
5
Department of Pathology, University College London Hospitals, 21 University Street, London WC1 6JJ, UK.
6
Advanced Sequencing Facility, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
7
Department of Nuclear Medicine, University College London Hospitals, 235 Euston Road, Fitzrovia, London, NW1 2BU, UK.
8
Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
9
Harvard Medical School, Boston, Massachusetts 02115, USA.
10
Tumour Profiling Unit Genomics Facility, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
11
Renal and Skin Units, The Royal Marsden Hospital, London SW3 6JJ, UK.
12
Department of Oncology, University College London Hospitals, 250 Euston Road, London NW1 2BU, UK.
13
Department of Cardiothoracic Surgery, University College London Hospitals, 235 Euston Road, Fitzrovia, London NW1 2BU, UK.
14
Department of Respiratory Medicine, University College London Hospitals, 235 Euston Road, Fitzrovia, London NW1 2BU, UK.
15
Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, Rayne Building, University College London, 5 University Street, London WC1E 6JF, UK.
16
Department of Radiology, University College London Hospitals, 235 Euston Road, Fitzrovia, London NW1 2BU, UK.
17
Institute of Cancer Studies, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
18
The Christie Hospital, Manchester M20 4BX, UK.
19
Department of Cardiothoracic Surgery, University Hospital South Manchester, Manchester M23 9LT, UK.
20
Department of Pathology, University Hospital South Manchester, Manchester M23 9LT, UK.
21
North West Lung Centre, University Hospital South Manchester, Manchester M23 9LT, UK.
22
Department of Thoracic Surgery, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK.
23
Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK. University College London Hospitals NHS Foundation Trust, London, UK.
24
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
25
Department of Cellular Pathology, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK.
26
Department of Medical Oncology, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK.
27
Department of Cardiothoracic Surgery, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen AB25 2ZD, UK.
28
Department of Pathology, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen AB25 2ZD, UK.
29
Department of Respiratory Medicine, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK.
30
Department of Radiology, Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK.
31
Department of Thoracic Surgery, Glenfield Hospital, Leicester LE3 9QP, UK.
32
Department of Radiotherapy, North Middlesex University Hospital, London N18 1QX, UK.
33
Department of Respiratory Medicine, Royal Free Hospital, Pond Street, London NW3 2QG, UK.
34
Department of Respiratory Medicine, Barnet and Chase Farm Hospitals, Wellhouse Lane, Barnet EN5 3DJ, UK.
35
Department of Respiratory Medicine, The Princess Alexandra Hospital, Hamstel Road, Harlow CM20 1QX, UK.
36
Department of Clinical Oncology, St.Luke's Cancer Centre, Royal Surrey County Hospital, Guildford GU2 7XX, UK.
37
Department of Pathology, Ashford and St. Peter's Hospital, Guildford Road, Chertsey, Surrey KT16 0PZ, UK.
38
Department of Respiratory Medicine, Ashford and St. Peter's Hospital, Guildford Road, Chertsey, Surrey KT16 0PZ, UK.
39
Department of Radiology, Ashford and St. Peter's Hospital, Guildford Road, Chertsey, Surrey KT16 0PZ, UK.
40
Department of Clinical Oncology, Velindre Hospital, Cardiff CF14 2TL, UK.
41
Department of Cardiothoracic Surgery, University Hospital of Wales, Cardiff CF14 4XW, UK.
42
Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Heath Park, Cardiff, UK.
43
Department of Radiology, University Hospital Llandough, Cardiff CF64 2XX, UK.
44
Department of Respiratory Medicine, University Hospital Llandough, Cardiff CF64 2XX, UK.
45
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.
46
Department of Respiratory Medicine, The Whittington Hospital NHS Trust, London, N19 5NF, UK.
47
University College London, Cancer Research UK and UCL Cancer Trials Centre, London W1T 4TJ, UK.
48
Centre for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.
49
Computational Health Informatics Program (CHIP), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
50
MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, 1091 Budapest, Hungary.
51
Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
52
Bill Lyons Informatics Centre, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6DD, UK.
53
Department of Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
54
Cancer Immunology Unit, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6DD, UK.
55
Research Department of Haematology, University College Cancer Institute, London WC1E 6DD, UK.
56
Cancer Genomics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
57
Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium.
58
Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
59
Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215-5450, USA.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT03004755.

PMID:
28445469
PMCID:
PMC5812436
DOI:
10.1038/nature22364
[Indexed for MEDLINE]
Free PMC Article

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