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Genomic signatures as predictive biomarkers of homologous recombination deficiency in ovarian cancer

  • Adriaan Vanderstichele
    Correspondence
    Corresponding author: Adriaan Vanderstichele, University Hospitals Leuven, Department of Gynaecology and Obstetrics, Herestraat 49, 3000, Leuven, Belgium.
    Affiliations
    Department of Gynaecology and Obstetrics, University Hospitals Leuven, Belgium

    Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
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  • Pieter Busschaert
    Affiliations
    Department of Gynaecology and Obstetrics, University Hospitals Leuven, Belgium

    Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
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  • Siel Olbrecht
    Affiliations
    Department of Gynaecology and Obstetrics, University Hospitals Leuven, Belgium

    Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
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  • Diether Lambrechts
    Affiliations
    Center for Cancer Biology, VIB, Leuven, Belgium

    Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium
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  • Ignace Vergote
    Affiliations
    Department of Gynaecology and Obstetrics, University Hospitals Leuven, Belgium

    Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
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Published:September 23, 2017DOI:https://doi.org/10.1016/j.ejca.2017.08.029

      Highlights

      • Leveraging DNA repair as a target for cancer therapy requires biomarkers of DNA repair pathway activity and deficiency (e.g. homologous recombination deficiency in ovarian cancer).
      • Patterns of mutational and structural chromosomal variation arise on a background of defective DNA repair.
      • Signatures of base substitutions and structural chromosomal variation can be extracted from annotated cohorts and correlate with specific DNA repair deficiencies.
      • The identification of genomic signatures in well-annotated patient cohorts will serve future attempts to stratify tumors based on the functionality of their DNA repair pathways.

      Abstract

      DNA repair deficiency is a common hallmark of many cancers and is increasingly recognised as a target for cancer therapeutics. Selecting patients for these treatments requires a functional assessment of multiple redundant DNA repair pathways. With the advent of whole-genome sequencing of cancer genomes, it is increasingly recognised that multiple signatures of mutational and chromosomal alterations can be correlated with specific DNA repair defects. The clinical relevance of this approach is underlined by the use of poly-(ADP-ribose) polymerase inhibitors (PARPi) in homologous recombination (HR) deficient high-grade serous ovarian cancers. Beyond deleterious mutations in HR-related genes such as BRCA1/2, it is recognised that HR deficiency endows ovarian cancers with specific signatures of base substitutions and structural chromosomal variation. Multiple metrics quantifying loss-of-heterozygosity (LOH) events were proposed and implemented in trials with PARPi. However, it was shown that some of the HR-deficient cases, i.e. CDK12–mutated tumours, were not associated with high LOH-based scores, but with distinct patterns of genomic alterations such as tandem duplication. Therefore, more complex signatures of structural genomic variation were identified and quantified. Ultimately, optimal prediction models for treatments targeting DNA repair will need to integrate multiples of these genomic signatures and will also need to assess multiple resistance mechanisms such as genomic reversion events that partially or fully re-activate DNA repair.

      Keywords

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