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Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy

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Listed:
  • John M. Findlay

    (Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive
    Oxford Oesophagogastric Centre, Churchill Hospital, Oxford University Hospitals NHS Trust
    Genomic Medicine Theme, Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive)

  • Francesc Castro-Giner

    (Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive)

  • Seiko Makino

    (Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive
    Genomic Medicine Theme, Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive)

  • Emily Rayner

    (Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive
    Genomic Medicine Theme, Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive)

  • Christiana Kartsonaki

    (Old Road Campus Research Building
    Oxford Institute for Radiation Oncology, Old Road Campus Research Building)

  • William Cross

    (Evolution and Cancer Laboratory, Bart’s Cancer Institute, Queen Mary University of London, Charterhouse Square)

  • Michal Kovac

    (Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive)

  • Danny Ulahannan

    (Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive)

  • Claire Palles

    (Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive)

  • Richard S. Gillies

    (Oxford Oesophagogastric Centre, Churchill Hospital, Oxford University Hospitals NHS Trust)

  • Thomas P. MacGregor

    (Oxford Oesophagogastric Centre, Churchill Hospital, Oxford University Hospitals NHS Trust)

  • David Church

    (Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive)

  • Nicholas D. Maynard

    (Oxford Oesophagogastric Centre, Churchill Hospital, Oxford University Hospitals NHS Trust)

  • Francesca Buffa

    (Old Road Campus Research Building
    Oxford Institute for Radiation Oncology, Old Road Campus Research Building)

  • Jean-Baptiste Cazier

    (Centre for Computational Biology, Haworth Building, and School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham)

  • Trevor A. Graham

    (Evolution and Cancer Laboratory, Bart’s Cancer Institute, Queen Mary University of London, Charterhouse Square)

  • Lai-Mun Wang

    (John Radcliffe Hospital, Oxford University Hospitals NHS Trust
    Cancer Theme, Oxford NIHR Comprehensive Biomedical Research Centre, Old Road Campus Research Building, Roosevelt Drive)

  • Ricky A. Sharma

    (Old Road Campus Research Building
    Oxford Institute for Radiation Oncology, Old Road Campus Research Building
    Cancer Theme, Oxford NIHR Comprehensive Biomedical Research Centre, Old Road Campus Research Building, Roosevelt Drive)

  • Mark Middleton

    (Old Road Campus Research Building
    Cancer Theme, Oxford NIHR Comprehensive Biomedical Research Centre, Old Road Campus Research Building, Roosevelt Drive)

  • Ian Tomlinson

    (Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive
    Genomic Medicine Theme, Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive)

Abstract

How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C>A and TT>CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful.

Suggested Citation

  • John M. Findlay & Francesc Castro-Giner & Seiko Makino & Emily Rayner & Christiana Kartsonaki & William Cross & Michal Kovac & Danny Ulahannan & Claire Palles & Richard S. Gillies & Thomas P. MacGrego, 2016. "Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11111
    DOI: 10.1038/ncomms11111
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