Blackhall, Fiona H
Summers, Yvonne J
Le Quesne, J
Van Loo, P
AffiliationCancer Research UK Lung Cancer Centre of Excellence London and Manchester
MetadataShow full item record
AbstractBackground 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 .).
CitationTracking the evolution of non-small-cell lung cancer. 2017, N Engl J Med
JournalThe New England Journal of Medicine
- Multiregion sequencing reveals the intratumor heterogeneity of driver mutations in TP53-driven non-small cell lung cancer.
- Authors: Zhang LL, Kan M, Zhang MM, Yu SS, Xie HJ, Gu ZH, Wang HN, Zhao SX, Zhou GB, Song HD, Zheng CX
- Issue date: 2017 Jan 1
- Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.
- Authors: de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, Jamal-Hanjani M, Shafi S, Murugaesu N, Rowan AJ, Grönroos E, Muhammad MA, Horswell S, Gerlinger M, Varela I, Jones D, Marshall J, Voet T, Van Loo P, Rassl DM, Rintoul RC, Janes SM, Lee SM, Forster M, Ahmad T, Lawrence D, Falzon M, Capitanio A, Harkins TT, Lee CC, Tom W, Teefe E, Chen SC, Begum S, Rabinowitz A, Phillimore B, Spencer-Dene B, Stamp G, Szallasi Z, Matthews N, Stewart A, Campbell P, Swanton C
- Issue date: 2014 Oct 10
- Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma.
- Authors: Dong LQ, Shi Y, Ma LJ, Yang LX, Wang XY, Zhang S, Wang ZC, Duan M, Zhang Z, Liu LZ, Zheng BH, Ding ZB, Ke AW, Gao DM, Yuan K, Zhou J, Fan J, Xi R, Gao Q
- Issue date: 2018 Jul
- The influence of TP53 mutations on the prognosis of patients with early stage non-small cell lung cancer may depend on the intratumor heterogeneity of the mutations.
- Authors: Lee SY, Jeon HS, Hwangbo Y, Jeong JY, Park JY, Lee EJ, Jin G, Shin KM, Yoo SS, Lee J, Lee EB, Cha SI, Kim CH, Park JY
- Issue date: 2015 Feb
- The impact of EGFR mutation status on outcomes in patients with resected stage I non-small cell lung cancers.
- Authors: Izar B, Sequist L, Lee M, Muzikansky A, Heist R, Iafrate J, Dias-Santagata D, Mathisen D, Lanuti M
- Issue date: 2013 Sep