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Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma

Author

Listed:
  • Olga Kondrashova

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Monique Topp

    (The Walter and Eliza Hall Institute of Medical Research
    Monash University)

  • Ksenija Nesic

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Elizabeth Lieschke

    (The Walter and Eliza Hall Institute of Medical Research)

  • Gwo-Yaw Ho

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Royal Women’s Hospital
    Peter MacCallum Cancer Centre)

  • Maria I. Harrell

    (University of Washington)

  • Giada V. Zapparoli

    (Olivia Newton-John Cancer Research Institute
    La Trobe University)

  • Alison Hadley

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Robert Holian

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Emma Boehm

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Valerie Heong

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Royal Women’s Hospital)

  • Elaine Sanij

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Richard B. Pearson

    (Peter MacCallum Cancer Centre
    The University of Melbourne
    University of Melbourne
    Monash University)

  • John J. Krais

    (Fox Chase Cancer Centre)

  • Neil Johnson

    (Fox Chase Cancer Centre)

  • Orla McNally

    (Royal Women’s Hospital)

  • Sumitra Ananda

    (Royal Women’s Hospital)

  • Kathryn Alsop

    (Peter MacCallum Cancer Centre)

  • Karla J. Hutt

    (Monash University)

  • Scott H. Kaufmann

    (Mayo Clinic)

  • Kevin K. Lin

    (Clovis Oncology)

  • Thomas C. Harding

    (Clovis Oncology)

  • Nadia Traficante

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Anna deFazio

    (Westmead Hospital)

  • Iain A. McNeish

    (Imperial College London, Kensington)

  • David D. Bowtell

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Elizabeth M. Swisher

    (University of Washington)

  • Alexander Dobrovic

    (Olivia Newton-John Cancer Research Institute
    La Trobe University
    University of Melbourne)

  • Matthew J. Wakefield

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Clare L. Scott

    (The Walter and Eliza Hall Institute of Medical Research
    Monash University
    Peter MacCallum Cancer Centre)

Abstract

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

Suggested Citation

  • Olga Kondrashova & Monique Topp & Ksenija Nesic & Elizabeth Lieschke & Gwo-Yaw Ho & Maria I. Harrell & Giada V. Zapparoli & Alison Hadley & Robert Holian & Emma Boehm & Valerie Heong & Elaine Sanij & , 2018. "Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05564-z
    DOI: 10.1038/s41467-018-05564-z
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    Cited by:

    1. Petra Brugge & Sarah C. Moser & Ivan Bièche & Petra Kristel & Sabrina Ibadioune & Alexandre Eeckhoutte & Roebi Bruijn & Eline Burg & Catrin Lutz & Stefano Annunziato & Julian Ruiter & Julien Masliah P, 2023. "Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Philip Smith & Thomas Bradley & Lena Morrill Gavarró & Teodora Goranova & Darren P. Ennis & Hasan B. Mirza & Dilrini Silva & Anna M. Piskorz & Carolin M. Sauer & Sarwah Al-Khalidi & Ionut-Gabriel Funi, 2023. "The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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