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

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, Osvaldas Vainauskas, Marina Parry, Mazlina Ismail, Wout Devlies, Anna Wingate, Mark Linch, Cristina Naceur-Lombardelli, Charles Swanton, Mariam Jamal-Hanjani, Stefano Lise, Shahneen Sandhu and Gerhardt Attard ()
Additional contact information
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
Stephen Q. Wong: Peter MacCallum Cancer Centre
Scott Williams: University of Melbourne
Anupama Pasam: Peter MacCallum Cancer Centre
Anna Trigos: Peter MacCallum Cancer Centre
Blanca Trujillo: University College London Cancer Institute
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
Cristina Naceur-Lombardelli: University College London Cancer Institute
Charles Swanton: University College London Cancer Institute
Mariam Jamal-Hanjani: 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

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40315-9

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