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

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 x 10(-8) and 6.4 x 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. The heterogeneity of androgen receptor (AR) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.

Automated summary

By analyzing the genomic complexity of AR across lethal metastases from 10 prostate cancer patients, the study finds diverse and patient-specific AR gene alterations, as well as independent acquisition of related genomic changes within an individual and the existence of AR-neutral clones. The study also confirms a common clone of origin across metastases and identifies clusters of metastases with diverged autosomal copy number alterations. These findings provide insights into the heterogeneity and evolution of AR alterations in metastatic prostate cancer.