Phylogenetic ctDNA analysis depicts early stage lung cancer evolution

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.

Metadata

Item Type:	Article
Authors/Creators:	Abbosh, C Birkbak, NJ Wilson, GA Jamal-Hanjani, M Constantin, T Salari, R Quesne, JL Moore, DA Veeriah, S Rosenthal, R Marafioti, T Kirkizlar, E Watkins, TBK McGranahan, N Ward, S Martinson, L Riley, J Fraioli, F Bakir, MA GrÖnroos, E Zambrana, F Endozo, R Bi, WL Fennessy, FM Sponer, N Johnson, D Laycock, J Shafi, S Czyzewska-Khan, J Rowan, A Chambers, T Matthews, N Turajlic, S Hiley, C Lee, SM Forster, MD Ahmad, T Falzon, M Borg, E Lawrence, D Hayward, M Kolvekar, S Panagiotopoulos, N Janes, SM Thakrar, R Ahmed, A Blackhall, F Summers, Y Hafez, D Naik, A Ganguly, A Kareht, S Shah, R Joseph, L Quinn, AM Crosbie, P Naidu, B Middleton, G Langman, G Trotter, S Nicolson, M Remmen, H Kerr, K Chetty, M Gomersall, L Fennell, DA Nakas, A Rathinam, S Anand, G Khan, S Russell, P Ezhil, V Ismail, B Irvin-sellers, M Prakash, V Lester, JF Kornaszewska, M Attanoos, R Adams, H Davies, H Oukrif, D Akarca, AU Hartley, JA Lowe, HL Lock, S Iles, N Bell, H Ngai, Y Elgar, G Szallasi, Z Schwarz, RF Herrero, J Stewart, A Quezada, SA Van Loo, P Dive, C Lin, CJ Rabinowitz, M Aerts, HJWL Hackshaw, A Shaw, JA Zimmermann, BG 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, G Birkbak, NJ Watkins, TBK McGranahan, N Horswell, S Al Bakir, M 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 Al Bakir, M Joshi, K Furness, A Aissa, AB Wong, YNS Georgiou, A Quezada, S 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, M 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, P Moss, S Idries, F Joseph, L Bishop, P Chaturved, A Marie Quinn, A 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, D Shaw, JA Le Quesne, J Moore, D Thomas, A Walter, H Riley, J Martinson, L Nakas, A Rathinam, S Monteiro, W Marshall, H Nelson, L Bennett, J Riley, J Primrose, L Martinson, L Anand, G Khan, S Amadi, A Nicolson, M Kerr, K Palmer, S Remmen, H Miller, J Buchan, K Chetty, M Gomersall, L Lester, J 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 Tavares Barbosa, M Bowman, A Jordan, S Rice, A Raubenheimer, H Proli, C Elena Cufari, M 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 https://orcid.org/0000-0002-7935-5327 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 Rabinowitz, M Aerts, HJWL Dentro, S Dessimoz, C Swanton, C Jamal-Hanjani, M Abbosh, C Shiu, K-K Bridgewater, J Hochauser, D Van Loo, P Quezada, S Beck, S Parker, P Walczak, H Enver, T Falzon, M Proctor, I Sinclair, R Lok, C-W Novelli, M Marafioti, T Borg, E Mitchison, M Trevisan, G Lynch, M Brandner, S Gishen, F Tookman, A Stone, P Sterling, C Larkin, J Turajlic, S Attard, G Eeles, R Foster, C Bova, S Sottoriva, A Chowdhury, S Ashish, C Spicer, J Stares, M Lynch, J Caldas, C Brenton, J Fitzgerald, R Jimenez-Linan, M Provenzano, E Cluroe, A Stewart, G Watts, C Gilbertson, R McDermott, U Tavare, S Maughan, T Tomlinson, I Campbell, P McNeish, I Biankin, A Chambers, A Fraser, S Oien, K Krebs, M Blackhall, F Summers, Y Dive, C Marais, R Carter, L Nonaka, D Quinn, AM Dhomen, N Fennell, D Le Quesne, J Moore, D Shaw, J Naidu, B Baijal, S Tanchel, B Langman, G Collard, M Cockcroft, P Taylor, J Bancroft, H Kerr, A Middleton, G Webb, J Kadiri, S Colloby, P Olisemeke, B Wilson, R Ottensmeier, C Harrison, D Loda, M Flanagan, A Wilcox, M McKenzie, M Hackshaw, A Lederman, J Sharp, A Farrelly, L Swanton, C
Copyright, Publisher and Additional Information:	© 2018 Nature Publishing Group.
Keywords:	Diagnostic markers; Metastasis; Non-small-cell lung cancer; Predictive markers; Tumour heterogeneity
Dates:	Accepted: 13 April 2017 Published (online): 26 April 2017 Published: 26 April 2017
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	31 May 2018 14:03
Last Modified:	31 May 2018 16:31
Published Version:	https://doi.org/10.1038/nature22364
Status:	Published
Publisher:	Nature Publishing Group
Refereed:	Yes
Identification Number:	10.1038/nature22364
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:131252

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Phylogenetic ctDNA analysis depicts early stage lung cancer evolution

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