Treatment-mediated selection of lethal prostate cancer clones defined by copy number architectures

<title>Abstract</title> Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient relationships of metastases that evade treatment, we performed genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (<italic>AR</italic>) on 142 metastatic regions from 10 organs harvested post-mortem from nine men who died from prostate cancer. We identified diverse and patient-unique alterations clustering around the <italic>AR</italic> 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 <italic>AR</italic>-neutral clones. Using the genomic boundaries of pan-autosome copy number change, we confirmed 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 and cluster-specific <italic>AR</italic> gene architectures. Copy number boundaries identified treatment-selected clones with distinct lethal trajectories.