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JOURNAL ARTICLE

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
New England Journal of Medicine 2017 June 1, 376 (22): 2109-2121
28445112

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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