Helmholtz Gemeinschaft


Tracking the evolution of non-small-cell lung cancer

Official URL:https://doi.org/10.1056/NEJMoa1616288
PubMed:View item in PubMed
Creators Name:Jamal-Hanjani, M. and Wilson, G.A. and McGranahan, N. and Birkbak, N.J. and Watkins, T.B.K. and Veeriah, S. and Shafi, S. and Johnson, D.H. and Mitter, R. and Rosenthal, R. and Salm, M. and Horswell, S. and Escudero, M. and Matthews, N. and Rowan, A. and Chambers, T. and Moore, D.A. and Turajlic, S. and Xu, H. and Lee, S.-M. and Forster, M.D. and Ahmad, T. and Hiley, C.T. and Abbosh, C. and Falzon, M. and Borg, E. and Marafioti, T. and Lawrence, D. and Hayward, M. and Kolvekar, S. and Panagiotopoulos, N. and Janes, S.M. and Thakrar, R. and Ahmed, A. and Blackhall, F. and Summers, Y. and Shah, R. and Joseph, L. and Quinn, A.M. and Crosbie, P.A. and Naidu, B. and Middleton, G. and Langman, G. and Trotter, S. and Nicolson, M. and Remmen, H. and Kerr, K. and Chetty, M. and Gomersall, L. and Fennell, D.A. and Nakas, A. and Rathinam, S. and Anand, G. and Khan, S. and Russell, P. and Ezhil, V. and Ismail, B. and Irvin-Sellers, M. and Prakash, V. and Lester, J.F. and Kornaszewska, M. and Attanoos, R. and Adams, H. and Davies, H. and Dentro, S. and Taniere, P. and O'Sullivan, B. and Lowe, H.L. and Hartley, J.A. and Iles, N. and Bell, H. and Ngai, Y. and Shaw, J.A. and Herrero, J. and Szallasi, Z. and Schwarz, R.F. and Stewart, A. and Quezada, S.A. and Le Quesne, J. and Van Loo, P. and Dive, C. and Hackshaw, A. and Swanton, C.
Journal Title:New England Journal of Medicine
Journal Abbreviation:N Engl J Med
Page Range:2109-2121
Date:1 June 2017
Keywords:Chromosomal Instability, DNA Copy Number Variations, DNA Sequence Analysis, Disease-Free Survival, Exome, Genetic Heterogeneity, Local Neoplasm Recurrence, Lung Neoplasms, Molecular Evolution, Mutation, Non-Small-Cell Lung Carcinoma, Phylogeny, Prognosis, Prospective Studies, Risk Factors
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.
Publisher:Massachusetts Medical Society (U.S.A.)
Item Type:Article

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