The evolution of lung cancer and impact of subclonal selection in TRACERx

Alexander M. Frankell, Michelle Dietzen, Maise Al Bakir, Emilia L. Lim, Takahiro Karasaki, Sophia Ward, Selvaraju Veeriah, Emma Colliver, Ariana Huebner, Abigail Bunkum, Mark S. Hill, Kristiana Grigoriadis, David A. Moore, James R. M. Black, Wing Kin Liu, Kerstin Thol, Oriol Pich, Thomas B. K. Watkins, Cristina Naceur-Lombardelli, Daniel E. Cook, Roberto Salgado, Gareth A. Wilson, Chris Bailey, Mihaela Angelova, Robert Bentham, Carlos Martínez-Ruiz, Christopher Abbosh, Andrew G. Nicholson, John Quesne, Dhruva Biswas, Rachel Rosenthal, Clare Puttick, Sonya Hessey, Claudia Lee, Paulina Prymas, Antonia Toncheva, Jon Smith, Wei Xing, Jerome Nicod, Gillian Price, Keith M. Kerr, Babu Naidu, Gary Middleton, Kevin G. Blyth, Dean A. Fennell, Martin D. Forster, Siow Ming Lee, Mary Falzon, Madeleine Hewish, Michael J. Shackcloth, Eric Lim, Sarah Benafif, Peter Russell, Ekaterini Boleti, Matthew G. Krebs, Jason F. Lester, Dionysis Papadatos-Pastos, Tanya Ahmad, Ricky M. Thakrar, David Lawrence, Neal Navani, Sam M. Janes, Caroline Dive, Fiona H. Blackhall, Yvonne Summers, Judith Cave, Teresa Marafioti, Javier Herrero, Sergio A. Quezada, Karl S. Peggs, Roland F. Schwarz, Peter Loo, Daniël M. Miedema, Nicolai J. Birkbak, Crispin T. Hiley, Allan Hackshaw, Simone Zaccaria, Mariam Jamal-Hanjani (), Nicholas McGranahan () and Charles Swanton ()
Additional contact information
Alexander M. Frankell: The Francis Crick Institute
Michelle Dietzen: The Francis Crick Institute
Maise Al Bakir: The Francis Crick Institute
Emilia L. Lim: The Francis Crick Institute
Takahiro Karasaki: The Francis Crick Institute
Sophia Ward: The Francis Crick Institute
Selvaraju Veeriah: University College London Cancer Institute
Emma Colliver: The Francis Crick Institute
Ariana Huebner: The Francis Crick Institute
Abigail Bunkum: University College London Cancer Institute
Mark S. Hill: The Francis Crick Institute
Kristiana Grigoriadis: The Francis Crick Institute
David A. Moore: The Francis Crick Institute
James R. M. Black: University College London Cancer Institute
Wing Kin Liu: University College London Cancer Institute
Kerstin Thol: University College London Cancer Institute
Oriol Pich: The Francis Crick Institute
Thomas B. K. Watkins: The Francis Crick Institute
Cristina Naceur-Lombardelli: University College London Cancer Institute
Daniel E. Cook: The Francis Crick Institute
Roberto Salgado: ZAS Hospitals
Gareth A. Wilson: The Francis Crick Institute
Chris Bailey: The Francis Crick Institute
Mihaela Angelova: The Francis Crick Institute
Robert Bentham: University College London Cancer Institute
Carlos Martínez-Ruiz: University College London Cancer Institute
Christopher Abbosh: University College London Cancer Institute
Andrew G. Nicholson: Guy’s and St Thomas’ NHS Foundation Trust
John Quesne: Cancer Research UK Beatson Institute
Dhruva Biswas: The Francis Crick Institute
Rachel Rosenthal: The Francis Crick Institute
Clare Puttick: The Francis Crick Institute
Sonya Hessey: University College London Cancer Institute
Claudia Lee: The Francis Crick Institute
Paulina Prymas: University College London Cancer Institute
Antonia Toncheva: University College London Cancer Institute
Jon Smith: The Francis Crick Institute
Wei Xing: The Francis Crick Institute
Jerome Nicod: The Francis Crick Institute
Gillian Price: Aberdeen Royal Infirmary NHS Grampian
Keith M. Kerr: University of Aberdeen
Babu Naidu: University of Birmingham
Gary Middleton: University Hospital Birmingham NHS Foundation Trust
Kevin G. Blyth: Cancer Research UK Beatson Institute
Dean A. Fennell: University of Leicester
Martin D. Forster: University College London Cancer Institute
Siow Ming Lee: University College London Cancer Institute
Mary Falzon: University College London Hospitals
Madeleine Hewish: Royal Surrey Hospital, Royal Surrey Hospitals NHS Foundation Trust
Michael J. Shackcloth: Liverpool Heart and Chest Hospital
Eric Lim: Imperial College London
Sarah Benafif: University College London Hospitals
Peter Russell: Princess Alexandra Hospital, The Princess Alexandra Hospital NHS Trust
Ekaterini Boleti: Royal Free Hospital, Royal Free London NHS Foundation Trust
Matthew G. Krebs: The University of Manchester and The Christie NHS Foundation Trust
Jason F. Lester: Swansea Bay University Health Board
Dionysis Papadatos-Pastos: University College London Hospitals
Tanya Ahmad: University College London Hospitals
Ricky M. Thakrar: University College London Hospitals
David Lawrence: University College London Hospital NHS Trust
Neal Navani: University College London Hospitals
Sam M. Janes: University College London
Caroline Dive: University of Manchester
Fiona H. Blackhall: The University of Manchester and The Christie NHS Foundation Trust
Yvonne Summers: The University of Manchester and The Christie NHS Foundation Trust
Judith Cave: University Hospital Southampton NHS Foundation Trust
Teresa Marafioti: University College London Hospitals
Javier Herrero: University College London Cancer Institute
Sergio A. Quezada: University College London Cancer Institute
Karl S. Peggs: University College London Hospitals
Roland F. Schwarz: University of Cologne
Peter Loo: The University of Texas MD Anderson Cancer Center
Daniël M. Miedema: University of Amsterdam
Nicolai J. Birkbak: The Francis Crick Institute
Crispin T. Hiley: The Francis Crick Institute
Allan Hackshaw: Cancer Research UK and UCL Cancer Trials Centre
Simone Zaccaria: University College London Cancer Institute
Mariam Jamal-Hanjani: University College London Cancer Institute
Nicholas McGranahan: University College London Cancer Institute
Charles Swanton: The Francis Crick Institute

Nature, 2023, vol. 616, issue 7957, 525-533

Abstract: Abstract Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

Date: 2023
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DOI: 10.1038/s41586-023-05783-5

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