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The role of tandem duplicator phenotype in tumour evolution in high-grade serous ovarian cancer

Authors

  • Charlotte KY Ng,

    1. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
    2. Department of Oncology, University of Cambridge, Cambridge,CB2 0XZ, UK
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  • Susanna L Cooke,

    1. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
    Current affiliation:
    1. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK.
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  • Kevin Howe,

    1. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
    Current affiliation:
    1. European Bioinformatics Institute, Hinxton, Cambridgeshire, CB10 1SD, UK.
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  • Scott Newman,

    1. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
    2. Hutchison/MRC Research Centre and Department of Pathology, University of Cambridge, Box 197, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XZ, UK
    Current affiliation:
    1. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
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  • Jian Xian,

    1. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
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  • Jillian Temple,

    1. Department of Oncology, University of Cambridge, Cambridge,CB2 0XZ, UK
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  • Elizabeth M Batty,

    1. Hutchison/MRC Research Centre and Department of Pathology, University of Cambridge, Box 197, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XZ, UK
    Current affiliation:
    1. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford, OX1 3 TG, UK.
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  • Jessica CM Pole,

    1. Hutchison/MRC Research Centre and Department of Pathology, University of Cambridge, Box 197, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XZ, UK
    Current affiliation:
    1. BlueGnome Ltd, Breaks House, Mill Court, Great Shelford, Cambridge, CB22 5LD, UK.
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  • Simon P Langdon,

    1. Breakthrough Breast Unit and Division of Pathology, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK
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  • Paul AW Edwards,

    1. Hutchison/MRC Research Centre and Department of Pathology, University of Cambridge, Box 197, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XZ, UK
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  • James D Brenton

    Corresponding author
    1. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
    2. Department of Oncology, University of Cambridge, Cambridge,CB2 0XZ, UK
    • Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
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  • No conflicts of interest were declared.

Abstract

High-grade serous ovarian carcinoma (HGSOC) is characterized by genomic instability, ubiquitous TP53 loss, and frequent development of platinum resistance. Loss of homologous recombination (HR) is a mutator phenotype present in 50% of HGSOCs and confers hypersensitivity to platinum treatment. We asked which other mutator phenotypes are present in HGSOC and how they drive the emergence of platinum resistance. We performed whole-genome paired-end sequencing on a model of two HGSOC cases, each consisting of a pair of cell lines established before and after clinical resistance emerged, to describe their structural variants (SVs) and to infer their ancestral genomes as the SVs present within each pair. The first case (PEO1/PEO4), with HR deficiency, acquired translocations and small deletions through its early evolution, but a revertant BRCA2 mutation restoring HR function in the resistant lineage re-stabilized its genome and reduced platinum sensitivity. The second case (PEO14/PEO23) had 216 tandem duplications and did not show evidence of HR or mismatch repair deficiency. By comparing the cell lines to the tissues from which they originated, we showed that the tandem duplicator mutator phenotype arose early in progression in vivo and persisted throughout evolution in vivo and in vitro, which may have enabled continual evolution. From the analysis of SNP array data from 454 HGSOC cases in The Cancer Genome Atlas series, we estimate that 12.8% of cases show patterns of aberrations similar to the tandem duplicator, and this phenotype is mutually exclusive with BRCA1/2 carrier mutations. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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