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

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 × 10-8 and 6.4 × 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.
Authors:
AMM Hasan, P Cremaschi, D Wetterskog, A Jayaram, SQ Wong, S Williams, A Pasam, A Trigos, B Trujillo, E Grist, S Friedrich, O Vainauskas, M Parry, M Ismail, W Devlies, A Wingate, M Linch, C Naceur-Lombardelli, PEACE consortium, C Swanton, M Jamal-Hanjani, S Lise, S Sandhu, G Attard
Journal:
Nat Commun
Citation info:
14(1):4823
Publication date:
10th Aug 2023
Full text
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