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

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

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de Bruin, Elza C., McGranahan, Nicholas, Mitter, Richard, Salm, Max, Wedge, David C., Yates, Lucy, Jamal-Hanjani, Mariam, Shafi, Seema, Murugaesu, Nirupa, Rowan, Andrew J., Grönroos, Eva, Muhammad, Madiha A., Horswell, Stuart, Gerlinger, Marco, Varela, Ignacio, Jones, David, Marshall, John, Voet, Thierry, Van Loo, Peter, Rassl, Doris M., Rintoul, Robert C., Janes, Sam M., Lee, Siow-Ming, Forster, Martin, Ahmad, Tanya, Lawrence, David, Falzon, Mary, Capitanio, Arrigo, Harkins, Timothy T., Lee, Clarence C., Tom, Warren, Teefe, Enock, Chen, Shann-Ching, Begum, Sharmin, Rabinowitz, Adam, Phillimore, Benjamin, Spencer-Dene, Bradley, Stamp, Gordon, Szallasi, Zoltan, Matthews, Nik, Stewart, Aengus, Campbell, Peter, Swanton, Charles·2014·Science

DOI 10.1126/science.1253462

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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.

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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
ORCID: McGranahan, Nicholas
Mitter, Richard
Salm, Max
Wedge, David C.
Yates, Lucy
Murugaesu, Nirupa
Rowan, Andrew J.
Horswell, Stuart
Gerlinger, Marco
Varela, Ignacio
Jones, David
Voet, Thierry
Rassl, Doris M.
Rintoul, Robert C.
Janes, Sam M.
Lee, Siow-Ming
Forster, Martin
Lawrence, David
Falzon, Mary
Capitanio, Arrigo
Harkins, Timothy T.
Lee, Clarence C.
Teefe, Enock
Begum, Sharmin
Rabinowitz, Adam
Stamp, Gordon
Matthews, Nik
Campbell, Peter
Swanton, Charles
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2014-10-10
Volume: 346
Issue: 6206
Pages: 251-256
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1253462
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: green
hdl.handle.net
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

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