Tracking the Evolution of Non-Small-Cell Lung Cancer
Mariam Jamal-Hanjani, Gareth A Wilson, Nicholas McGranahan, Nicolai J Birkbak, Thomas B K Watkins, Selvaraju Veeriah, Seema Shafi, Diana H Johnson, Richard Mitter, Rachel Rosenthal, Max Salm, Stuart Horswell, Mickael Escudero, Nik Matthews, Andrew Rowan, Tim Chambers, David A Moore, Samra Turajlic, Hang Xu, Siow-Ming Lee, Martin D Forster, Tanya Ahmad, Crispin T Hiley, Christopher Abbosh, Mary Falzon, Elaine Borg, Teresa Marafioti, David Lawrence, Martin Hayward, Shyam Kolvekar, Nikolaos Panagiotopoulos, Sam M Janes, Ricky Thakrar, Asia Ahmed, Fiona Blackhall, Yvonne Summers, Rajesh Shah, Leena Joseph, Anne M 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, Stefan Dentro, Philippe Taniere, Brendan O'Sullivan, Helen L Lowe, John A Hartley, Natasha Iles, Harriet Bell, Yenting Ngai, Jacqui A Shaw, Javier Herrero, Zoltan Szallasi, Roland F Schwarz, Aengus Stewart, Sergio A Quezada, John Le Quesne, Peter Van Loo, Caroline Dive, Allan Hackshaw, Charles Swanton, 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, Mariam Jamal-Hanjani, Gareth A Wilson, Nicholas McGranahan, Nicolai J Birkbak, Thomas B K Watkins, Selvaraju Veeriah, Seema Shafi, Diana H Johnson, Richard Mitter, Rachel Rosenthal, Max Salm, Stuart Horswell, Mickael Escudero, Nik Matthews, Andrew Rowan, Tim Chambers, David A Moore, Samra Turajlic, Hang Xu, Siow-Ming Lee, Martin D Forster, Tanya Ahmad, Crispin T Hiley, Christopher Abbosh, Mary Falzon, Elaine Borg, Teresa Marafioti, David Lawrence, Martin Hayward, Shyam Kolvekar, Nikolaos Panagiotopoulos, Sam M Janes, Ricky Thakrar, Asia Ahmed, Fiona Blackhall, Yvonne Summers, Rajesh Shah, Leena Joseph, Anne M 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, Stefan Dentro, Philippe Taniere, Brendan O'Sullivan, Helen L Lowe, John A Hartley, Natasha Iles, Harriet Bell, Yenting Ngai, Jacqui A Shaw, Javier Herrero, Zoltan Szallasi, Roland F Schwarz, Aengus Stewart, Sergio A Quezada, John Le Quesne, Peter Van Loo, Caroline Dive, Allan Hackshaw, Charles Swanton, 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
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 .).
Source: PubMed