Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

Christopher Abbosh, Nicolai J. Birkbak, Gareth A. Wilson, Mariam Jamal-Hanjani, Tudor Constantin, Raheleh Salari, John Le Quesne, David A. Moore, Selvaraju Veeriah, Rachel Rosenthal, Teresa Marafioti, Eser Kirkizlar, Thomas B. K. Watkins, Nicholas McGranahan, Sophia Ward, Luke Martinson, Joan Riley, Francesco Fraioli, Maise Al Bakir, Eva Grönroos, Francisco Zambrana, Raymondo Endozo, Wenya Linda Bi, Fiona M. Fennessy, Nicole Sponer, Diana Johnson, Joanne Laycock, Seema Shafi, Justyna Czyzewska-Khan, Andrew Rowan, Tim Chambers, Nik Matthews, Samra Turajlic, Crispin Hiley, Siow Ming Lee, Martin D. Forster, Tanya Ahmad, Mary Falzon, Elaine Borg, David Lawrence, Martin Hayward, Shyam Kolvekar, Nikolaos Panagiotopoulos, Sam M. Janes, Ricky Thakrar, Asia Ahmed, Fiona Blackhall, Yvonne Summers, Dina Hafez, Ashwini Naik, Apratim Ganguly, Stephanie Kareht, Rajesh Shah, Leena Joseph, Anne Marie Quinn, Phil A. Crosbie, Babu Naidu, Gary Middleton, Gerald Langman, Simon Trotter, Marianne Nicolson, Hardy Remmen, Keith Kerr, Mahendran Chetty, Lesley Gomersall, Dean A. Fennell, Apostolos Nakas, Sridhar Rathinam, Girija Anand, Sajid Khan, Peter Russell, Veni Ezhil, Babikir Ismail, Melanie Irvin-Sellers, Vineet Prakash, Jason F. Lester, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Dahmane Oukrif, Ayse U. Akarca, John A. Hartley, Helen L. Lowe, Sara Lock, Natasha Iles, Harriet Bell, Yenting Ngai, Greg Elgar, Zoltan Szallasi, Roland F. Schwarz, Javier Herrero, Aengus Stewart, Sergio A. Quezada, Karl S. Peggs, Peter Van Loo, Caroline Dive, C. Jimmy Lin, Matthew Rabinowitz, Hugo J. W. L. Aerts, Allan Hackshaw, Jacqui A. Shaw, Bernhard G. Zimmermann and Charles Swanton ()
Additional contact information
Christopher Abbosh: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Nicolai J. Birkbak: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Gareth A. Wilson: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Mariam Jamal-Hanjani: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Tudor Constantin: Natera Inc.
Raheleh Salari: Natera Inc.
John Le Quesne: Cancer Studies, University of Leicester
David A. Moore: Cancer Studies, University of Leicester
Selvaraju Veeriah: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Rachel Rosenthal: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Teresa Marafioti: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Eser Kirkizlar: Natera Inc.
Thomas B. K. Watkins: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Nicholas McGranahan: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Sophia Ward: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Luke Martinson: Cancer Studies, University of Leicester
Joan Riley: Cancer Studies, University of Leicester
Francesco Fraioli: University College London Hospitals
Maise Al Bakir: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute
Eva Grönroos: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute
Francisco Zambrana: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Raymondo Endozo: University College London Hospitals
Wenya Linda Bi: Brigham and Women’s Hospital
Fiona M. Fennessy: Brigham and Women’s Hospital
Nicole Sponer: Natera Inc.
Diana Johnson: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Joanne Laycock: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Seema Shafi: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Justyna Czyzewska-Khan: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Andrew Rowan: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute
Tim Chambers: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute
Nik Matthews: Advanced Sequencing Facility, The Francis Crick Institute
Samra Turajlic: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute
Crispin Hiley: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Siow Ming Lee: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Martin D. Forster: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Tanya Ahmad: University College London Hospitals
Mary Falzon: University College London Hospitals
Elaine Borg: University College London Hospitals
David Lawrence: University College London Hospitals
Martin Hayward: University College London Hospitals
Shyam Kolvekar: University College London Hospitals
Nikolaos Panagiotopoulos: University College London Hospitals
Sam M. Janes: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Ricky Thakrar: University College London Hospitals
Asia Ahmed: University College London Hospitals
Fiona Blackhall: Institute of Cancer Studies, University of Manchester
Yvonne Summers: The Christie Hospital
Dina Hafez: Natera Inc.
Ashwini Naik: Natera Inc.
Apratim Ganguly: Natera Inc.
Stephanie Kareht: Natera Inc.
Rajesh Shah: University Hospital South Manchester
Leena Joseph: University Hospital South Manchester
Anne Marie Quinn: University Hospital South Manchester
Phil A. Crosbie: North West Lung Centre, University Hospital South Manchester
Babu Naidu: Birmingham Heartlands Hospital
Gary Middleton: Institute of Immunology and Immunotherapy, University of Birmingham
Gerald Langman: Birmingham Heartlands Hospital
Simon Trotter: Birmingham Heartlands Hospital
Marianne Nicolson: Aberdeen University Medical School and Aberdeen Royal Infirmary
Hardy Remmen: Aberdeen University Medical School and Aberdeen Royal Infirmary
Keith Kerr: Aberdeen University Medical School and Aberdeen Royal Infirmary
Mahendran Chetty: Aberdeen University Medical School and Aberdeen Royal Infirmary
Lesley Gomersall: Aberdeen University Medical School and Aberdeen Royal Infirmary
Dean A. Fennell: Cancer Studies, University of Leicester
Apostolos Nakas: Glenfield Hospital
Sridhar Rathinam: Glenfield Hospital
Girija Anand: North Middlesex University Hospital
Sajid Khan: Royal Free Hospital
Peter Russell: The Princess Alexandra Hospital
Veni Ezhil: St.Luke’s Cancer Centre, Royal Surrey County Hospital
Babikir Ismail: Ashford and St. Peter’s Hospital
Melanie Irvin-Sellers: Ashford and St. Peter’s Hospital
Vineet Prakash: Ashford and St. Peter’s Hospital
Jason F. Lester: Velindre Hospital
Malgorzata Kornaszewska: University Hospital of Wales
Richard Attanoos: University Hospital of Wales and Cardiff University
Haydn Adams: University Hospital Llandough
Helen Davies: University Hospital Llandough
Dahmane Oukrif: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
Ayse U. Akarca: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
John A. Hartley: University College London Experimental Cancer Medicine Centre GCLP Facility, University College London Cancer Institute
Helen L. Lowe: University College London Experimental Cancer Medicine Centre GCLP Facility, University College London Cancer Institute
Sara Lock: The Whittington Hospital NHS Trust
Natasha Iles: University College London, Cancer Research UK and UCL Cancer Trials Centre
Harriet Bell: University College London, Cancer Research UK and UCL Cancer Trials Centre
Yenting Ngai: University College London, Cancer Research UK and UCL Cancer Trials Centre
Greg Elgar: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute
Zoltan Szallasi: Centre for Biological Sequence Analysis, Technical University of Denmark
Roland F. Schwarz: Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine
Javier Herrero: Bill Lyons Informatics Centre, University College London Cancer Institute
Aengus Stewart: The Francis Crick Institute
Sergio A. Quezada: Cancer Immunology Unit, University College London Cancer Institute
Karl S. Peggs: Cancer Immunology Unit, University College London Cancer Institute
Peter Van Loo: Cancer Genomics Laboratory, The Francis Crick Institute
Caroline Dive: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute
C. Jimmy Lin: Natera Inc.
Matthew Rabinowitz: Natera Inc.
Hugo J. W. L. Aerts: Brigham and Women’s Hospital
Allan Hackshaw: University College London, Cancer Research UK and UCL Cancer Trials Centre
Jacqui A. Shaw: Cancer Studies, University of Leicester
Bernhard G. Zimmermann: Natera Inc.
Charles Swanton: Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London Cancer Institute

Nature, 2017, vol. 545, issue 7655, 446-451

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22364

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