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

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. MacGregor, David Church, Nicholas D. Maynard, Francesca Buffa, Jean-Baptiste Cazier, Trevor A. Graham, Lai-Mun Wang, Ricky A. Sharma, Mark Middleton and Ian Tomlinson ()
Additional contact information
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
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
Emily Rayner: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive
Christiana Kartsonaki: 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
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
Ricky A. Sharma: Old Road Campus Research Building
Mark Middleton: Old Road Campus Research Building
Ian Tomlinson: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11111

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