. 2017 Jun 1;376(22):2109-2121.

doi: 10.1056/NEJMoa1616288. Epub 2017 Apr 26.

Tracking the Evolution of Non-Small-Cell Lung Cancer

Mariam Jamal-Hanjani¹, Gareth A Wilson¹, Nicholas McGranahan¹, Nicolai J Birkbak¹, Thomas B K Watkins¹, Selvaraju Veeriah¹, Seema Shafi¹, Diana H Johnson¹, Richard Mitter¹, Rachel Rosenthal¹, Max Salm¹, Stuart Horswell¹, Mickael Escudero¹, Nik Matthews¹, Andrew Rowan¹, Tim Chambers¹, David A Moore¹, Samra Turajlic¹, Hang Xu¹, Siow-Ming Lee¹, Martin D Forster¹, Tanya Ahmad¹, Crispin T Hiley¹, Christopher Abbosh¹, Mary Falzon¹, Elaine Borg¹, Teresa Marafioti¹, David Lawrence¹, Martin Hayward¹, Shyam Kolvekar¹, Nikolaos Panagiotopoulos¹, Sam M Janes¹, Ricky Thakrar¹, Asia Ahmed¹, Fiona Blackhall¹, Yvonne Summers¹, Rajesh Shah¹, Leena Joseph¹, Anne M Quinn¹, Phil A Crosbie¹, Babu Naidu¹, Gary Middleton¹, Gerald Langman¹, Simon Trotter¹, Marianne Nicolson¹, Hardy Remmen¹, Keith Kerr¹, Mahendran Chetty¹, Lesley Gomersall¹, Dean A Fennell¹, Apostolos Nakas¹, Sridhar Rathinam¹, Girija Anand¹, Sajid Khan¹, Peter Russell¹, Veni Ezhil¹, Babikir Ismail¹, Melanie Irvin-Sellers¹, Vineet Prakash¹, Jason F Lester¹, Malgorzata Kornaszewska¹, Richard Attanoos¹, Haydn Adams¹, Helen Davies¹, Stefan Dentro¹, Philippe Taniere¹, Brendan O'Sullivan¹, Helen L Lowe¹, John A Hartley¹, Natasha Iles¹, Harriet Bell¹, Yenting Ngai¹, Jacqui A Shaw¹, Javier Herrero¹, Zoltan Szallasi¹, Roland F Schwarz¹, Aengus Stewart¹, Sergio A Quezada¹, John Le Quesne¹, Peter Van Loo¹, Caroline Dive¹, Allan Hackshaw¹, Charles Swanton¹; TRACERx Consortium

Collaborators, Affiliations

Collaborators

TRACERx Consortium:
Justyna Czyzewska-Khan, Joanne Laycock, Leticia Bosshard-Carter, Gerald Goh, Pat Gorman, Nirupa Murugaesu, Robert E Hynds, Jacki Goldman, Richard Kevin Stone, Tamara Denner, Greg Elgar, Sophia Ward, Jennifer Biggs, Marta Costa, Sharmin Begum, Ben Phillimore, Emma Nye, Sofia Graca, Maise Al Bakir, Kroopa Joshi, Andrew Furness, Assma Ben Aissa, Yien Ning Sophia Wong, Andy Georgiou, Davide Patrini, Celia Simeon, Gemma Hector, Amy Smith, Marie Aranda, Marco Novelli, Dahmane Oukrif, Dionysis Papadatos-Pastos, Dawn Carnell, Ruheena Mendes, Jeremy George, Neal Navani, Magali Taylor, Penny Shaw, Junaid Choudhary, Raffaele Califano, Paul Taylor, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Stuart Moss, Faiza Idries, Paul Bishop, Anshuman Chaturved, Helen Doran, Angela Leek, Phil Harrison, Katrina Moore, Rachael Waddington, Juliette Novasio, Jane Rogan, Elaine Smith, Jonathan Tugwood, Ged Brady, Dominic G Rothwell, Francesca Chemi, Jackie Pierce, Sakshi Gulati, Mary Bellamy, Hollie Bancroft, Amy Kerr, Salma Kadiri, Joanne Webb, Madava Djearaman, William Monteiro, Hilary Marshall, Louise Nelson, Jonathan Bennett, Joan Riley, Lindsay Primrose, Luke Martinson, Anita Amadi, Shirley Palmer, Joy Miller, Keith Buchan, Alison Edwards, Fiona Morgan, Sara Lock, Azmina Verjee, Mairead MacKenzie, Maggie Wilcox, Sean Smith, Nicole Gower, Christian Ottensmeier, Serena Chee, Benjamin Johnson, Aiman Alzetani, Emily Shaw, 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, Kelvin Lau, Michael Sheaff, Peter Schmid, John Conibear, Teresa Light, Tracey Horey, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews, Yota Kitsanta, Kim Suvarna, Patricia Fisher, Allah Dino Keerio, Michael Shackcloth, John Gosney, Pieter Postmus, Sarah Feeney, Julius Asante-Siaw, Tudor Constatin, Raheleh Salari, Nicole Sponer, Ashwini Naik, Bernhard Zimmermann, Hugo J W L Aerts, Christophe Dessimoz, Karl Peggs

Affiliation

¹ From the Cancer Research UK Lung Cancer Centre of Excellence (M.J.-H., G.A.W., N. McGranahan, N.J.B., S.V., S.S., D.H.J., R.R., S.-M.L., M.D.F., C.A., S.M.J., C.D., C.S.), London and Manchester, Good Clinical Laboratory Practice Facility, University College London (UCL) Experimental Cancer Medicine Centre (H.L.L., J.A.H.), Bill Lyons Informatics Centre (J.H.), and Cancer Immunology Unit (S.A.Q.), UCL Cancer Institute, the Translational Cancer Therapeutics Laboratory (G.A.W., N. McGranahan, N.J.B., T.B.K.W., A.R., T.C., S. Turajlic, H.X., C.T.H., C.S.), Department of Bioinformatics and Biostatistics (R.M., M.S., S.H., M.E., A.S.), Advanced Sequencing Facility (N. Matthews), and Cancer Genomics Laboratory (S.D., P.V.L.), Francis Crick Institute, the Renal and Skin Units, Royal Marsden Hospital (S. Turajlic), the Departments of Medical Oncology (M.J.-H., S.-M.L., M.D.F., T.A., C.A., C.S.), Pathology (M.F., E.B., T.M.), Cardiothoracic Surgery (D.L., M.H., S. Kolvekar, N.P.), Respiratory Medicine (S.M.J., R.T.), and Radiology (A.A.), UCL Hospitals, Lungs for Living, UCL Respiratory, UCL (S.M.J.), the Department of Radiotherapy, North Middlesex University Hospital (G.A.), the Department of Respiratory Medicine, Royal Free Hospital (S. Khan), and UCL Cancer Research UK and Cancer Trials Centre (N.I., H.B., Y.N., A.H.), London, Cancer Studies, University of Leicester (D.A.M., D.A.F., J.A.S., J.L.Q.), the Department of Thoracic Surgery, Glenfield Hospital (A.N., S.R.), and the Medical Research Center Toxicology Unit (J.L.Q.), Leicester, the Institute of Cancer Studies, University of Manchester (F.B.), the Christie Hospital (F.B., Y.S.), the Departments of Cardiothoracic Surgery (R.S.) and Pathology (L.J., A.M.Q.) and the North West Lung Centre (P.A.C.), University Hospital of South Manchester, and Cancer Research UK Manchester Institute (C.D.), Manchester, the Departments of Thoracic Surgery (B.N.) and Cellular Pathology (G.L., S. Trotter), Birmingham Heartlands Hospital, Molecular Pathology Diagnostic Services, Queen Elizabeth Hospital (P.T., B.O.), and Institute of Immunology and Immunotherapy, University of Birmingham (G.M.), Birmingham, the Departments of Medical Oncology (M.N.), Cardiothoracic Surgery (H.R.), Pathology (K.K.), Respiratory Medicine (M.C.), and Radiology (L.G.), Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen, the Department of Respiratory Medicine, Barnet and Chase Farm Hospitals, Barnet (S. Khan), the Department of Respiratory Medicine, Princess Alexandra Hospital, Harlow (P.R.), the Department of Clinical Oncology, St. Luke's Cancer Centre, Guildford (V.E.), the Departments of Pathology (B.I.), Respiratory Medicine (M.I.-S.), and Radiology (V.P.), Ashford and St. Peters' Hospitals, Surrey, the Department of Clinical Oncology, Velindre Hospital (J.F.L.), the Departments of Radiology (H.A.) and Respiratory Medicine (H.D.), University Hospital Llandough, the Departments of Pathology (R.A.) and Cardiothoracic Surgery (M.K.), University Hospital of Wales, and Cardiff University (R.A.), Cardiff, and Wellcome Trust Sanger Institute, Hinxton, and Big Data Institute, University of Oxford, Oxford (S.D.) - all in the United Kingdom; the Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby (Z.S.); the Computational Health Informatics Program, Boston Children's Hospital and Harvard Medical School, Boston (Z.S.); MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary (Z.S.); Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin (R.F.S.); and the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.).

PMID: 28445112
DOI: 10.1056/NEJMoa1616288

Free article

Tracking the Evolution of Non-Small-Cell Lung Cancer

Mariam Jamal-Hanjani et al. N Engl J Med. 2017.

Free article

. 2017 Jun 1;376(22):2109-2121.

doi: 10.1056/NEJMoa1616288. Epub 2017 Apr 26.

Authors

Collaborators

TRACERx Consortium:
Justyna Czyzewska-Khan, Joanne Laycock, Leticia Bosshard-Carter, Gerald Goh, Pat Gorman, Nirupa Murugaesu, Robert E Hynds, Jacki Goldman, Richard Kevin Stone, Tamara Denner, Greg Elgar, Sophia Ward, Jennifer Biggs, Marta Costa, Sharmin Begum, Ben Phillimore, Emma Nye, Sofia Graca, Maise Al Bakir, Kroopa Joshi, Andrew Furness, Assma Ben Aissa, Yien Ning Sophia Wong, Andy Georgiou, Davide Patrini, Celia Simeon, Gemma Hector, Amy Smith, Marie Aranda, Marco Novelli, Dahmane Oukrif, Dionysis Papadatos-Pastos, Dawn Carnell, Ruheena Mendes, Jeremy George, Neal Navani, Magali Taylor, Penny Shaw, Junaid Choudhary, Raffaele Califano, Paul Taylor, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Stuart Moss, Faiza Idries, Paul Bishop, Anshuman Chaturved, Helen Doran, Angela Leek, Phil Harrison, Katrina Moore, Rachael Waddington, Juliette Novasio, Jane Rogan, Elaine Smith, Jonathan Tugwood, Ged Brady, Dominic G Rothwell, Francesca Chemi, Jackie Pierce, Sakshi Gulati, Mary Bellamy, Hollie Bancroft, Amy Kerr, Salma Kadiri, Joanne Webb, Madava Djearaman, William Monteiro, Hilary Marshall, Louise Nelson, Jonathan Bennett, Joan Riley, Lindsay Primrose, Luke Martinson, Anita Amadi, Shirley Palmer, Joy Miller, Keith Buchan, Alison Edwards, Fiona Morgan, Sara Lock, Azmina Verjee, Mairead MacKenzie, Maggie Wilcox, Sean Smith, Nicole Gower, Christian Ottensmeier, Serena Chee, Benjamin Johnson, Aiman Alzetani, Emily Shaw, 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, Kelvin Lau, Michael Sheaff, Peter Schmid, John Conibear, Teresa Light, Tracey Horey, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews, Yota Kitsanta, Kim Suvarna, Patricia Fisher, Allah Dino Keerio, Michael Shackcloth, John Gosney, Pieter Postmus, Sarah Feeney, Julius Asante-Siaw, Tudor Constatin, Raheleh Salari, Nicole Sponer, Ashwini Naik, Bernhard Zimmermann, Hugo J W L Aerts, Christophe Dessimoz, Karl Peggs

Affiliation

¹ From the Cancer Research UK Lung Cancer Centre of Excellence (M.J.-H., G.A.W., N. McGranahan, N.J.B., S.V., S.S., D.H.J., R.R., S.-M.L., M.D.F., C.A., S.M.J., C.D., C.S.), London and Manchester, Good Clinical Laboratory Practice Facility, University College London (UCL) Experimental Cancer Medicine Centre (H.L.L., J.A.H.), Bill Lyons Informatics Centre (J.H.), and Cancer Immunology Unit (S.A.Q.), UCL Cancer Institute, the Translational Cancer Therapeutics Laboratory (G.A.W., N. McGranahan, N.J.B., T.B.K.W., A.R., T.C., S. Turajlic, H.X., C.T.H., C.S.), Department of Bioinformatics and Biostatistics (R.M., M.S., S.H., M.E., A.S.), Advanced Sequencing Facility (N. Matthews), and Cancer Genomics Laboratory (S.D., P.V.L.), Francis Crick Institute, the Renal and Skin Units, Royal Marsden Hospital (S. Turajlic), the Departments of Medical Oncology (M.J.-H., S.-M.L., M.D.F., T.A., C.A., C.S.), Pathology (M.F., E.B., T.M.), Cardiothoracic Surgery (D.L., M.H., S. Kolvekar, N.P.), Respiratory Medicine (S.M.J., R.T.), and Radiology (A.A.), UCL Hospitals, Lungs for Living, UCL Respiratory, UCL (S.M.J.), the Department of Radiotherapy, North Middlesex University Hospital (G.A.), the Department of Respiratory Medicine, Royal Free Hospital (S. Khan), and UCL Cancer Research UK and Cancer Trials Centre (N.I., H.B., Y.N., A.H.), London, Cancer Studies, University of Leicester (D.A.M., D.A.F., J.A.S., J.L.Q.), the Department of Thoracic Surgery, Glenfield Hospital (A.N., S.R.), and the Medical Research Center Toxicology Unit (J.L.Q.), Leicester, the Institute of Cancer Studies, University of Manchester (F.B.), the Christie Hospital (F.B., Y.S.), the Departments of Cardiothoracic Surgery (R.S.) and Pathology (L.J., A.M.Q.) and the North West Lung Centre (P.A.C.), University Hospital of South Manchester, and Cancer Research UK Manchester Institute (C.D.), Manchester, the Departments of Thoracic Surgery (B.N.) and Cellular Pathology (G.L., S. Trotter), Birmingham Heartlands Hospital, Molecular Pathology Diagnostic Services, Queen Elizabeth Hospital (P.T., B.O.), and Institute of Immunology and Immunotherapy, University of Birmingham (G.M.), Birmingham, the Departments of Medical Oncology (M.N.), Cardiothoracic Surgery (H.R.), Pathology (K.K.), Respiratory Medicine (M.C.), and Radiology (L.G.), Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen, the Department of Respiratory Medicine, Barnet and Chase Farm Hospitals, Barnet (S. Khan), the Department of Respiratory Medicine, Princess Alexandra Hospital, Harlow (P.R.), the Department of Clinical Oncology, St. Luke's Cancer Centre, Guildford (V.E.), the Departments of Pathology (B.I.), Respiratory Medicine (M.I.-S.), and Radiology (V.P.), Ashford and St. Peters' Hospitals, Surrey, the Department of Clinical Oncology, Velindre Hospital (J.F.L.), the Departments of Radiology (H.A.) and Respiratory Medicine (H.D.), University Hospital Llandough, the Departments of Pathology (R.A.) and Cardiothoracic Surgery (M.K.), University Hospital of Wales, and Cardiff University (R.A.), Cardiff, and Wellcome Trust Sanger Institute, Hinxton, and Big Data Institute, University of Oxford, Oxford (S.D.) - all in the United Kingdom; the Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby (Z.S.); the Computational Health Informatics Program, Boston Children's Hospital and Harvard Medical School, Boston (Z.S.); MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary (Z.S.); Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin (R.F.S.); and the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.).

PMID: 28445112
DOI: 10.1056/NEJMoa1616288

Abstract

Background: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.

Methods: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival.

Results: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10^-4), which remained significant in multivariate analysis.

Conclusions: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

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Liquid-biopsies success highlights power of combining basic and clinical research.
[No authors listed] [No authors listed] Nature. 2017 Apr 26;544(7651):393. doi: 10.1038/544393a. Nature. 2017. PMID: 28447660 No abstract available.
Lung cancer: Tracing tumour evolution.
Romero D. Romero D. Nat Rev Clin Oncol. 2017 Jul;14(7):391. doi: 10.1038/nrclinonc.2017.73. Epub 2017 May 16. Nat Rev Clin Oncol. 2017. PMID: 28508874 No abstract available.
Lung Cancer: A Wily Genetic Opponent.
Hsu PP, Shaw AT. Hsu PP, et al. Cell. 2017 May 18;169(5):777-779. doi: 10.1016/j.cell.2017.05.001. Cell. 2017. PMID: 28525750
Cancer genomics: Tracking cancer evolution.
Perdigoto C. Perdigoto C. Nat Rev Genet. 2017 Jul;18(7):391. doi: 10.1038/nrg.2017.43. Epub 2017 May 22. Nat Rev Genet. 2017. PMID: 28529335 No abstract available.
Seeing the Forest through the Phylogenetic Tree.
Robles AI, Zenklusen JC. Robles AI, et al. N Engl J Med. 2017 Jun 1;376(22):2190-2191. doi: 10.1056/NEJMe1704618. N Engl J Med. 2017. PMID: 28564575 No abstract available.
TRACERx: Tracking tumor evolution to impact the course of lung cancer.
Negrao MV, Quek K, Zhang J, Sepesi B. Negrao MV, et al. J Thorac Cardiovasc Surg. 2018 Mar;155(3):1199-1202. doi: 10.1016/j.jtcvs.2017.10.134. Epub 2017 Nov 16. J Thorac Cardiovasc Surg. 2018. PMID: 29331175 No abstract available.
A richer understanding of intratumoral heterogeneity: single-cell genomics put it within reach.
Li X, Hou J. Li X, et al. J Thorac Dis. 2018 Mar;10(3):1178-1182. doi: 10.21037/jtd.2018.03.17. J Thorac Dis. 2018. PMID: 29707265 Free PMC article. No abstract available.

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Tracking the Evolution of Non-Small-Cell Lung Cancer

Collaborators

Affiliation

Tracking the Evolution of Non-Small-Cell Lung Cancer

Authors

Collaborators

Affiliation

Abstract

Comment in

MeSH terms

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous