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

Jamal-Hanjani, Mariam and Wilson, Gareth A and McGranahan, Nicholas and Birkbak, Nicolai J and Watkins, Thomas B K and Veeriah, Selvaraju and Shafi, Seema and Johnson, Diana H and Mitter, Richard and Rosenthal, Rachel and Salm, Max and Horswell, Stuart and Escudero, Mickael and Matthews, Nik and Rowan, Andrew and Chambers, Tim and Moore, David A and Turajlic, Samra and Xu, Hang and Lee, Siow-Ming and Forster, Martin D and Ahmad, Tanya and Hiley, Crispin T and Abbosh, Christopher and Falzon, Mary and Borg, Elaine and Marafioti, Teresa and Lawrence, David and Hayward, Martin and Kolvekar, Shyam and Panagiotopoulos, Nikolaos and Janes, Sam M and Thakrar, Ricky and Ahmed, Asia and Blackhall, Fiona and Summers, Yvonne and Shah, Rajesh and Joseph, Leena and Quinn, Anne M and Crosbie, Phil A and Naidu, Babu V and Middleton, Gary and Langman, Gerald and Trotter, Simon and Nicolson, Marianne and Remmen, Hardy and Kerr, Keith and Chetty, Mahendran and Gomersall, Lesley and Fennell, Dean A and Nakas, Apostolos and Rathinam, Sridhar and Anand, Girija and Khan, Sajid and Russell, Peter and Ezhil, Veni and Ismail, Babikir and Irvin-Sellers, Melanie and Prakash, Vineet and Lester, Jason F and Kornaszewska, Malgorzata and Attanoos, Richard and Adams, Haydn and Davies, Helen and Dentro, Stefan and Taniere, Philippe and O'Sullivan, Brendan and Lowe, Helen L and Hartley, John A and Iles, Natasha and Bell, Harriet and Ngai, Yenting and Shaw, Jacqui A and Herrero, Javier and Szallasi, Zoltan and Schwarz, Roland F and Stewart, Aengus and Quezada, Sergio A and Le Quesne, John and Van Loo, Peter and Dive, Caroline and Hackshaw, Allan and Swanton, Charles (2017) Tracking the Evolution of Non-Small-Cell Lung Cancer. The New England journal of medicine, 376 (22). pp. 2109-2121. ISSN 1533-4406. This article is available to all HEFT staff and students via ASK Discovery tool by using their HEFT Athens login IDs

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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 .).

Item Type: Article
Additional Information: This article is available to all HEFT staff and students via ASK Discovery tool by using their HEFT Athens login IDs
Subjects: QZ Pathology. Oncology
Divisions: Planned IP Care > Oncology and Clinical Haematology
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Depositing User: Mrs Caroline Tranter
Date Deposited: 23 Jun 2017 15:44
Last Modified: 23 Jun 2017 15:44

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