Copy number architectures define treatment-mediated selection of lethal prostate cancer clones
Journal Title
Nature Communications
Publication Type
Research article
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 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.
Keywords
Male; Humans; *DNA Copy Number Variations; *Prostatic Neoplasms/genetics/pathology; Receptors, Androgen/genetics; Genome; Genomics; Clone Cells/pathology
Department(s)
Laboratory Research; Medical Oncology; Radiation Oncology
PubMed ID
37563129
Open Access at Publisher's Site
https://doi.org/10.1038/s41467-023-40315-9
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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