Copy number architectures define treatment-mediated selection of lethal prostate cancer clones
- Author(s)
- Hasan, AMM; Cremaschi, P; Wetterskog, D; Jayaram, A; Wong, SQ; Williams, S; Pasam, A; Trigos, A; Trujillo, B; Grist, E; Friedrich, S; Vainauskas, O; Parry, M; Ismail, M; Devlies, W; Wingate, A; Linch, M; Naceur-Lombardelli, C; PEACE Consortium; Swanton, C; Jamal-Hanjani, M; Lise, S; Sandhu, S; Attard, G;
- 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
- Publisher's Version
- https://doi.org/10.1038/s41467-023-40315-9
- 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.
Creation Date: 2023-12-20 12:23:23
Last Modified: 2023-12-20 12:24:27