Cited by 1,117Cancer Genomics and DiagnosticsLung Cancer Treatments and MutationsChromatin Remodeling and Cancer

Spatial and temporal diversity in genomic instability processes defines lung cancer evolution

Open access
de Bruin, Elza C., McGranahan, Nicholas, Mitter, Richard, Salm, Max, Wedge, David C., Yates, Lucy, Jamal-Hanjani, Mariam, Shafi, Seema +35 more·2014·Science

Abstract

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non–small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.

Integrity signals

Registry

Crossref · 10.1126/science.1253462

Cites

62 of 62 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • There is evidence that APOBEC-mediated mutagenesis fuels sub-clonal diversification and branched evolution.

    “While the full extent to which mutational processes account for unique combinations of somatic genomic alterations in NSCLC is currently unknown, there is evidence that APOBEC-mediated mutagenesis fuels sub-clonal diversification and branched evolution78, 79.”

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
de Bruin, E. C., McGranahan, N., Mitter, R., Salm, M., Wedge, D. C., Yates, L., Jamal-Hanjani, M., Shafi, S., Murugaesu, N., Rowan, A. J., Grönroos, E., Muhammad, M. A., Horswell, S., Gerlinger, M., Varela, I., Jones, D., Marshall, J., Voet, T., Van Loo, P., Rassl, D. M., Rintoul, R. C., Janes, S. M., Lee, S.-M., Forster, M., Ahmad, T., Lawrence, D., Falzon, M., Capitanio, A., Harkins, T. T., Lee, C. C., Tom, W., Teefe, E., Chen, S.-C., Begum, S., Rabinowitz, A., Phillimore, B., Spencer-Dene, B., Stamp, G., Szallasi, Z., Matthews, N., Stewart, A., Campbell, P., & Swanton, C.
Affiliations
  • Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK.
  • Cancer Research UK (GB)
  • Wellcome Sanger Institute (GB)
  • University of Cambridge (GB)
  • Cancer Research UK London Research Institute, London WC2A 3LY, UK.
  • Universidad de Cantabria (ES)
  • Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
  • Papworth Hospital NHS Foundation Trust (GB)
  • University College London (GB)
  • Thermo Fisher Scientific (United States) (US)
  • Technical University of Denmark, 2800 Kongens Lyngby, Denmark.
Corresponding author
  • McGranahan, Nicholas
  • Mitter, Richard
  • Salm, Max
  • Wedge, David C.
  • Yates, Lucy
  • Swanton, Charles
Venue
Science
Published
2014-10-10
Volume
346
Issue
6206
Pages
251-256
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2108371618
Cited by
1,117
References
62
Citations by year
2026: 38 · 2025: 43 · 2024: 59 · 2023: 82 · 2022: 82 · 2021: 86 · 2020: 99 · 2019: 113 · 2018: 111 · 2017: 145 · 2016: 131 · 2015: 119 · 2014: 9
FWCI
43.17
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • UCrea (University of Cantabria) (acceptedVersion, other-oa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Prostate Cancer Foundation
  • Breast Cancer Research Foundation
  • Wellcome Trust (091730, 105104, 088340)
  • Cancer Research UK (259303, A11590, A4688, A17786, 17001, A19310, 17786, 18377)
  • National Institute for Health and Care Research (CL-2011-18-001)
  • Academy of Medical Sciences (AMS-SGCL7-Murugaesu)
  • University College London
  • European Commission (259303)
  • Rosetrees Trust (M35-F1-CD1)
  • Fonds Wetenschappelijk Onderzoek
  • Ministerio de Economía y Competitividad
  • Vlaamse regering
  • National Institutes of Health
  • Medical Research Council
  • NIHR Cambridge Biomedical Research Centre
  • National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
non-small cell lung cancer, tumor evolution, intratumoral heterogeneity, driver mutations, copy number alterations, chromosomal translocation, APOBEC mutational signature, genome doubling, tumor latency, carcinogen exposure, genomic instability
MeSH terms
APOBEC-1 Deaminase, Carcinogens, Carcinoma, Non-Small-Cell Lung, Cytidine Deaminase, Humans, Lung Neoplasms, Mutation, Neoplasm Recurrence, Local, Prognosis, Smoking, Translocation, Genetic, Tumor Cells, Cultured, Gene Dosage, Genetic Heterogeneity, Evolution, Molecular, Genomic Instability

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review