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.
Nature communications. 2023 Aug 10*** epublish ***
A M Mahedi Hasan, Paolo Cremaschi, Daniel Wetterskog, Anuradha Jayaram, Stephen Q Wong, Scott Williams, Anupama Pasam, Anna Trigos, Blanca Trujillo, Emily Grist, Stefanie Friedrich, Osvaldas Vainauskas, Marina Parry, Mazlina Ismail, Wout Devlies, Anna Wingate, Mark Linch, Cristina Naceur-Lombardelli, PEACE consortium , Charles Swanton, Mariam Jamal-Hanjani, Stefano Lise, Shahneen Sandhu, Gerhardt Attard
University College London Cancer Institute, London, UK., Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia., Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK., University College London Cancer Institute, London, UK. .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37563129