The Francis Crick Institute
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Copy number architectures define treatment-mediated selection of lethal prostate cancer clones.

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journal contribution
posted on 2023-08-15, 08:30 authored by AM 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
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.


Crick (Grant ID: CC2041, Grant title: Swanton CC2041) Crick (Grant ID: CC2044, Grant title: Turajlic CC2044) Crick (Grant ID: CC2140, Grant title: Parker CC2140) Crick (Grant ID: CC2008, Grant title: Van Loo CC2008) Crick (Grant ID: CC1061, Grant title: STP Experimental Histopathology) Crick (Grant ID: CC1064, Grant title: STP Advanced Sequencing) Crick (Grant ID: CC1109, Grant title: STP BRF) Novo Nordisk UK Research Foundation (Grant ID: NNF15OC0016584, Grant title: NovoNordisk Foundation 16584) European Research Council (Grant ID: 835297 - PROTEUS, Grant title: ERC 835297 - PROTEUS)