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Science. 2014 Oct 10;346(6206):251-6. doi: 10.1126/science.1253462.

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

Author information

1
Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK.
2
Cancer Research UK London Research Institute, London WC2A 3LY, UK. Centre for Mathematics and Physics in the Life Science and Experimental Biology (CoMPLEX), University College London, London WC1E 6BT, UK.
3
Cancer Research UK London Research Institute, London WC2A 3LY, UK.
4
Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
5
Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. University of Cambridge, Cambridge CB2 1TN, UK.
6
Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
7
Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium.
8
Papworth Hospital NHS Foundation Trust, Cambridge CB23 3RE, UK.
9
Lungs for Living Research Centre, University College London, London WC1E 6BT, UK.
10
Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. University College London Hospitals, London NW1 2BU, UK.
11
University College London Hospitals, London NW1 2BU, UK.
12
Thermo Fisher Scientific, Carlsbad, CA 92008, USA.
13
Technical University of Denmark, 2800 Kongens Lyngby, Denmark. Children's Hospital Informatics Program, Harvard Medical School, Boston, MA 02115, USA.
14
Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. Cancer Research UK London Research Institute, London WC2A 3LY, UK. charles.swanton@cancer.org.uk.

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.

PMID:
25301630
PMCID:
PMC4636050
DOI:
10.1126/science.1253462
[Indexed for MEDLINE]
Free PMC Article

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