EGAGenomicsOtherhttps://ega-archive.org/studies/EGAS00001006598EGAEGA study EGAS00001006598CASCADE low-pass whole genome sequencing dataCASCADE tumour transcriptome dataCASCADE germline whole genome sequencing dataCASCADE tumour high-coverage whole genome sequencing datarestrictedEGAfalseTreatment-mediated selection of lethal prostate cancer clones defined by copy number architecturesDespite 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 (AR) 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 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 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. Autosome-defined clusters were characterized by cluster-specific AR gene architectures that in two index cases were topologically more congruent than by chance (p-values 0.03, 3.07x10-8). Integration with anatomical site suggested patterns of spread and points of genomic divergence. Copy number boundaries identified treatment-selected clones with putatively distinct lethal trajectories.2022-12-13 11:52:18EGAS000010065989606EGAD00001009492EGAD00001009491EGAD00001009493EGAD00001009494EGAC00001002865