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Copy number architectures define treatment-mediated selection of lethal prostate cancer clones

Author

Listed:
  • A. M. Mahedi Hasan

    (University College London Cancer Institute)

  • Paolo Cremaschi

    (University College London Cancer Institute)

  • Daniel Wetterskog

    (University College London Cancer Institute)

  • Anuradha Jayaram

    (University College London Cancer Institute
    University College London Hospitals)

  • Stephen Q. Wong

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Scott Williams

    (University of Melbourne)

  • Anupama Pasam

    (Peter MacCallum Cancer Centre)

  • Anna Trigos

    (Peter MacCallum Cancer Centre)

  • Blanca Trujillo

    (University College London Cancer Institute
    University College London Hospitals)

  • Emily Grist

    (University College London Cancer Institute)

  • Stefanie Friedrich

    (University College London Cancer Institute)

  • Osvaldas Vainauskas

    (University College London Cancer Institute)

  • Marina Parry

    (University College London Cancer Institute)

  • Mazlina Ismail

    (University College London Cancer Institute)

  • Wout Devlies

    (University College London Cancer Institute)

  • Anna Wingate

    (University College London Cancer Institute)

  • Mark Linch

    (University College London Cancer Institute
    University College London Hospitals)

  • Cristina Naceur-Lombardelli

    (University College London Cancer Institute)

  • Charles Swanton

    (University College London Cancer Institute
    The Francis Crick Institute
    University College London Hospitals)

  • Mariam Jamal-Hanjani

    (University College London Cancer Institute
    University College London Hospitals
    University College London Cancer Institute)

  • Stefano Lise

    (University College London Cancer Institute)

  • Shahneen Sandhu

    (Peter MacCallum Cancer Centre)

  • Gerhardt Attard

    (University College London Cancer Institute
    University College London Hospitals)

Abstract

Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10−8 and 6.4 × 10−4). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.

Suggested Citation

  • A. M. Mahedi Hasan & Paolo Cremaschi & Daniel Wetterskog & Anuradha Jayaram & Stephen Q. Wong & Scott Williams & Anupama Pasam & Anna Trigos & Blanca Trujillo & Emily Grist & Stefanie Friedrich & Osva, 2023. "Copy number architectures define treatment-mediated selection of lethal prostate cancer clones," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40315-9
    DOI: 10.1038/s41467-023-40315-9
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    References listed on IDEAS

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    1. D. J. Woodcock & E. Riabchenko & S. Taavitsainen & M. Kankainen & G. Gundem & D. S. Brewer & P. Ellonen & M. Lepistö & Y. A. Golubeva & A. C. Warner & T. Tolonen & J. Jasu & W. B. Isaacs & M. R. Emmer, 2020. "Prostate cancer evolution from multilineage primary to single lineage metastases with implications for liquid biopsy," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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