# Tracking the evolution of non-small-cell lung cancer

Source: https://onco.cc/key-papers/paper-jamal-hanjani-tracerx-evolution-nsclc-nejm-2017/  
OnCo record `paper-jamal-hanjani-tracerx-evolution-nsclc-nejm-2017` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

TRACERx sequenced several regions of 100 lung tumours instead of one. The driver mutations were usually everywhere in the tumour, but three quarters had later mutations present in only part of it, and the messier the tumour, the worse the outcome.

## Summary

The TRACERx consortium, reported by Jamal-Hanjani, Wilson, McGranahan and colleagues with Swanton as senior author, performed multiregion whole-exome sequencing on 100 early-stage non-small-cell lung cancers resected before systemic therapy, analysing 327 tumour regions.

It is the study that made intratumour heterogeneity a measurable prognostic variable rather than a caveat. The practical consequence is that a single biopsy describes a sample of a tumour, not the tumour, and that chromosomal instability rather than mutation count is what tracks with recurrence.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Tags: lung-evidence
- Journal: New England Journal of Medicine
- Year: 2017
- DOI: 10.1056/NEJMoa1616288
- Authors: Jamal-Hanjani M, Wilson GA, McGranahan N, et al.
- Findings: 327 tumour regions from 100 resected early-stage tumours were sequenced.; Driver mutations in EGFR, MET, BRAF and TP53 were almost always clonal, present in every region.; Heterogeneous driver alterations arising later in evolution were found in more than 75 percent of tumours, commonly in PIK3CA and NF1 and in chromatin modification and DNA damage response genes.; Genome doubling and ongoing chromosomal instability produced parallel evolution of driver copy-number changes, 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 equals 4.4 by 10 to the minus 4), significant in multivariate analysis.
- What it means: Why targeting a clonal driver works and targeting a subclonal one usually does not, and why a single-site biopsy can mislead. Chromosomal instability is now a candidate prognostic marker in its own right.
- Caveats: 100 patients with resected early-stage disease; it does not describe metastatic tumours, which have evolved further.; Whole-exome rather than whole-genome sequencing, so structural variation and non-coding drivers are under-sampled.; The heterogeneity-recurrence association is prognostic, not a validated clinical test, and nothing yet changes treatment on the basis of it.

## Sources

- N Engl J Med 2017: https://doi.org/10.1056/NEJMoa1616288
- PubMed: https://pubmed.ncbi.nlm.nih.gov/28445112/
- ClinicalTrials.gov NCT01888601: https://clinicaltrials.gov/study/NCT01888601

## Connected records

- key papers: [Genomic and evolutionary classification of lung cancer in never smokers](https://onco.cc/key-papers/paper-zhang-lung-cancer-never-smokers-nat-genet-2021/), [Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors](https://onco.cc/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/), [Lung adenocarcinoma promotion by air pollutants](https://onco.cc/key-papers/paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023/), [Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution](https://onco.cc/key-papers/paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017/)
- cancers: [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Resectable stage I to III non-small-cell lung cancer](https://onco.cc/cancers/resectable-nsclc/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/)
- technologies: [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- terms: [Driver mutation](https://onco.cc/terms/driver-mutation/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/)
- targets: [BRAF](https://onco.cc/targets/braf/), [EGFR](https://onco.cc/targets/egfr/), [MET](https://onco.cc/targets/met/), [TP53](https://onco.cc/targets/tp53/)
- institutions: [The Francis Crick Institute](https://onco.cc/institutions/francis-crick/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/)
- people: [Charles Swanton](https://onco.cc/people/charles-swanton/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- roadmaps: [Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/)
- ideas: [Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became](https://onco.cc/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/)

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