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N Engl J Med. 2017 Jun 1;376(22):2109-2121. doi: 10.1056/NEJMoa1616288. Epub 2017 Apr 26.

Tracking the Evolution of Non-Small-Cell Lung Cancer.

Collaborators (146)

Czyzewska-Khan J, Laycock J, Bosshard-Carter L, Goh G, Gorman P, Murugaesu N, Hynds RE, Goldman J, Stone RK, Denner T, Elgar G, Ward S, Biggs J, Costa M, Begum S, Phillimore B, Nye E, Graca S, Al Bakir M, Joshi K, Furness A, Ben Aissa A, Wong YN, Georgiou A, Patrini D, Simeon C, Hector G, Smith A, Aranda M, Novelli M, Oukrif D, Papadatos-Pastos D, Carnell D, Mendes R, George J, Navani N, Taylor M, Shaw P, Choudhary J, Califano R, Taylor P, Krysiak P, Rammohan K, Fontaine E, Booton R, Evison M, Moss S, Idries F, Bishop P, Chaturved A, Doran H, Leek A, Harrison P, Moore K, Waddington R, Novasio J, Rogan J, Smith E, Tugwood J, Brady G, Rothwell DG, Chemi F, Pierce J, Gulati S, Bellamy M, Bancroft H, Kerr A, Kadiri S, Webb J, Djearaman M, Monteiro W, Marshall H, Nelson L, Bennett J, Riley J, Primrose L, Martinson L, Amadi A, Palmer S, Miller J, Buchan K, Edwards A, Morgan F, Lock S, Verjee A, MacKenzie M, Wilcox M, 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, 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, Constatin T, Salari R, Sponer N, Naik A, Zimmermann B, Aerts HJ, Dessimoz C, Peggs K.

Author information

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.).



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.


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.


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.


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 number, NCT01888601 .).

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