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

Jamal-Hanjani, Mariam, Wilson, Gareth A, McGranahan, Nicholas, Birkbak, Nicolai J, Watkins, Thomas B K, Veeriah, Selvaraju, Shafi, Seema, Johnson, Diana H, Mitter, Richard, Rosenthal, Rachel, Salm, Max, Horswell, Stuart, Escudero, Mickael, Matthews, Nik, Rowan, Andrew, Chambers, Tim, Moore, David A, Turajlic, Samra, Xu, Hang, Lee, Siow-Ming, Forster, Martin D, Ahmad, Tanya, Hiley, Crispin T, Abbosh, Christopher, Falzon, Mary, Borg, Elaine, Marafioti, Teresa, Lawrence, David, Hayward, Martin, Kolvekar, Shyam, Panagiotopoulos, Nikolaos, Janes, Sam M, Thakrar, Ricky, Ahmed, Asia, Blackhall, Fiona, Summers, Yvonne, Shah, Rajesh, Joseph, Leena, Quinn, Anne M, Crosbie, Phil A, Naidu, Babu V, Middleton, Gary, Langman, Gerald, Trotter, Simon, Nicolson, Marianne, Remmen, Hardy, Kerr, Keith, Chetty, Mahendran, Gomersall, Lesley, Fennell, Dean A, Nakas, Apostolos, Rathinam, Sridhar, Anand, Girija, Khan, Sajid, Russell, Peter, Ezhil, Veni, Ismail, Babikir, Irvin-Sellers, Melanie, Prakash, Vineet, Lester, Jason F, Kornaszewska, Malgorzata, Attanoos, Richard, Adams, Haydn, Davies, Helen, Dentro, Stefan, Taniere, Philippe, O'Sullivan, Brendan, Lowe, Helen L, Hartley, John A, Iles, Natasha, Bell, Harriet, Ngai, Yenting, Shaw, Jacqui A, Herrero, Javier, Szallasi, Zoltan, Schwarz, Roland F, Stewart, Aengus, Quezada, Sergio A, Le Quesne, John, Van Loo, Peter, Dive, Caroline, 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 http://tinyurl.com/z795c8c by using their HEFT Athens login IDs

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Official URL: http://www.nejm.org/doi/full/10.1056/NEJMoa1616288

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 .).

Item Type: Article
Additional Information: This article is available to all HEFT staff and students via ASK Discovery tool http://tinyurl.com/z795c8c 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
URI: http://www.repository.uhblibrary.co.uk/id/eprint/1429

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