Journal article
Tracking the Evolution of Non-Small-Cell Lung Cancer
CRUK Lung Cancer Centre of Excellence1
Glenfield Hospital2
North Middlesex University Hospital NHS Trust3
Barnet and Chase Farm Hospitals NHS Trust4
The Princess Alexandra Hospital NHS Trust5
St. Luke's Cancer Centre6
Velindre Hospital7
University Hospital Llandough8
Cardiff University9
University of Oxford10
Queen Elizabeth Hospital11
University College London12
Department of Bio and Health Informatics, Technical University of Denmark13
Cancer Genomics, Department of Bio and Health Informatics, Technical University of Denmark14
Max Delbrück Center for Molecular Medicine in the Helmholtz Association15
KU Leuven16
Cancer Research UK17
University of Leicester18
The Francis Crick Institute19
University of Manchester20
Christie Hospital21
University Hospital of South Manchester22
University of Birmingham23
...and 13 moreBackground 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 .).
Language: | English |
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Year: | 2017 |
Pages: | 2109-2121 |
ISSN: | 15334406 and 00284793 |
Types: | Journal article |
DOI: | 10.1056/NEJMoa1616288 |
Carcinoma, Non-Small-Cell Lung Chromosomal Instability DNA Copy Number Variations Disease-Free Survival Evolution, Molecular Exome Female Genetic Heterogeneity Humans Lung Neoplasms Male Mutation Neoplasm Recurrence, Local Phylogeny Prognosis Prospective Studies Risk Factors Sequence Analysis, DNA