title: Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy.
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.
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.|Oxford Oesophagogastric Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford OX3 7LJ, UK.|Genomic Medicine Theme, Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Findlay
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Francesc
authors.identifier: http://orcid.org/0000-0001-6111-0754
authors.initials: F
authors.lastname: Castro-Giner
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.|Genomic Medicine Theme, Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Seiko
authors.initials: S
authors.lastname: Makino
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.|Genomic Medicine Theme, Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Rayner
authors.affiliation: Department of Oncology, Old Road Campus Research Building, Oxford OX3 7DQ, UK.|Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Christiana
authors.initials: C
authors.lastname: Kartsonaki
authors.affiliation: Evolution and Cancer Laboratory, Bart's Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: William
authors.initials: W
authors.lastname: Cross
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Michal
authors.initials: M
authors.lastname: Kovac
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Danny
authors.initials: D
authors.lastname: Ulahannan
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Palles
authors.affiliation: Oxford Oesophagogastric Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford OX3 7LJ, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Gillies
authors.affiliation: Oxford Oesophagogastric Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford OX3 7LJ, UK.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: MacGregor
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: David
authors.initials: D
authors.lastname: Church
authors.affiliation: Oxford Oesophagogastric Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford OX3 7LJ, UK.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Maynard
authors.affiliation: Department of Oncology, Old Road Campus Research Building, Oxford OX3 7DQ, UK.|Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Francesca
authors.identifier: http://orcid.org/0000-0003-0409-406X
authors.initials: F
authors.lastname: Buffa
authors.affiliation: Centre for Computational Biology, Haworth Building, and School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.affiliation: Evolution and Cancer Laboratory, Bart's Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Trevor A
authors.identifier: http://orcid.org/0000-0001-9582-1597
authors.initials: TA
authors.lastname: Graham
authors.affiliation: Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford OX3 9DU, UK.|Cancer Theme, Oxford NIHR Comprehensive Biomedical Research Centre, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Lai-Mun
authors.initials: LM
authors.lastname: Wang
authors.affiliation: Department of Oncology, Old Road Campus Research Building, Oxford OX3 7DQ, UK.|Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Oxford OX3 7DQ, UK.|Cancer Theme, Oxford NIHR Comprehensive Biomedical Research Centre, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Ricky A
authors.initials: RA
authors.lastname: Sharma
authors.affiliation: Department of Oncology, Old Road Campus Research Building, Oxford OX3 7DQ, UK.|Cancer Theme, Oxford NIHR Comprehensive Biomedical Research Centre, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Middleton
authors.affiliation: Molecular and Population Genetics Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.|Genomic Medicine Theme, Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Ian
authors.identifier: http://orcid.org/0000-0003-3037-1470
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060965:Clonal Evolution / Q000187:drug effects*; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000187:drug effects; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059472:Exome; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics / Q000378:metabolism; D035362:Transcription Factor TFIID / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C080336:CCND2 protein, human; D056742:Cyclin D2; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D051548:Histone Acetyltransferases; C069001:TATA-binding protein associated factor 250 kDa