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=4.4x10-4),
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 .).
