Copy number architectures define treatment-mediated selection of lethal prostate cancer clones
Authors: Hasan A. M. Mahedi , Cremaschi Paolo , Wetterskog Daniel , Jayaram Anuradha , Wong Stephen Q. , Williams Scott , Pasam Anupama , Trigos Anna , Trujillo Blanca , Grist Emily , Friedrich Stefanie , Vainauskas Osvaldas , Parry Marina , Ismail Mazlina , Devlies Wout , Wingate Anna , Linch Mark , Naceur-Lombardelli Cristina ,   PEACE consortium, Zaccaria Simone , Hessey Sonya , Shiu Kai-Keen , Bridgewater John , Hochhauser Daniel , Forster Martin , Lee Siow-Ming , Ahmad Tanya , Papadatos-Pastos Dionysis , Janes Sam , Van Loo Peter , Enfield Katey , McGranahan Nicholas , Huebner Ariana , Quezada Sergio , Beck Stephan , Parker Peter , Enver Tariq , Hynds Robert E. , Pearce David R. , Falzon Mary , Proctor Ian , Sinclair Ron , Lok Chi-wah , Rhodes Zoe , Moore David , Marafioti Teresa , Mitchison Miriam , Ellery Peter , Sivakumar Monica , Linch Mark , Brandner Sebastian , Rowan Andrew , Hiley Crispin , Veeriah Selvaraju , Shaw Heather , Naceur-Lombardelli Cristina , Toncheva Antonia , Prymas Paulina , Watkins Thomas B. K. , Bailey Chris , Martinez Ruiz Carlos , Litchfield Kevin , Al-Bakir Maise , Kanu Nnenna , Ward Sophia , Lim Emilia , Reading James , Chain Benny , Watkins Tom , Akay Melek , Flanagan Adrienne , Biswas Dhruva , Pich Oriol , Dietzen Michelle , Puttick Clare , Colliver Emma , Magness Alistair , Angelova Mihaela , Black James , Lucas Olivia , Hill William , Liu Wing-Kin , Frankell Alexander , Magno Neil , Athanasopoulou Foteini , Salgado Roberto , Lee Claudia , Grigoriadis Kristiana , Al-Sawaf Othman , Karasaki Takahiro , Bunkum Abigail , Noorani Imran , Benafif Sarah , Barbe Vittorio , Bola Supreet Kaur , Leone Gianmarco , Alifrangis Constantine , McGovern Ursula , Thol Kerstin , Gamble Samuel , Ung Seng Kuong , Sahwangarrom Teerapon , Marin Claudia Peinador , Wong Sophia , Pawlik Piotr , Lam Jie Min , Richard Corentin , Vendramin Roberto , Dijkstra Krijn , Rane Jayant , Nicod Jerome , Dwornik Angela , Bowles Kerry , Zaidi Rija , Gishen Faye , Stone Paddy , Stirling Caroline , Turajlic Samra , Larkin James , Pickering Lisa , Furness Andrew , Young Kate , Drake Will , Edmonds Kim , Hunter Nikki , Mangwende Mary , Pearce Karla , Grostate Lauren , Au Lewis , Spain Lavinia , Shepherd Scott , Yan Haixi , Shum Benjamin , Tippu Zayd , Hanley Brian , Spencer Charlotte , Emmerich Max , Gerard Camille , Schmitt Andreas Michael , Del Rosario Lyra , Carlyle Eleanor , Lewis Charlotte , Holt Lucy , Lucanas Analyn , O’Flaherty Molly , Hazell Steve , Mudhar Hardeep , Messiou Christina , Latifoltojar Arash , Fendler Annika , Byrne Fiona , Pallikonda Husayn , Lobon Irene , Coulton Alexander , Cattin Anne-Laure , Deng Daqi , Feng Hugang , Rowan Andew , Yousaf Nadia , Popat Sanjay , Curtis Olivia , Milner-Watts Charlotte , Stamp Gordon , Nye Emma , Murra Aida , Korteweg Justine , Kelly Denise , Terry Lauren , Biano Jennifer , Peat Kema , Kelly Kayleigh , Grieco Charlotte , Le Mo Linh , D’Arienzo Paolo Davide , Turay Emma , Hill Peter , Josephs Debra , Irshad Sheeba , Spicer James , Mahadeva Ula , Green Anna , Stewart Ruby , Wright Natasha , Pulman Georgina , Mitu Ruxandra , Phillips-Boyd Sherene , Enting Deborah , Rudman Sarah , Ghosh Sharmistha , Karapanagiotou Eleni , Pintus Elias , Tutt Andrew , Howlett Sarah , Brenton James , Caldas Carlos , Fitzgerald Rebecca , Jimenez-Linan Merche , Provenzano Elena , Cluroe Alison , Paterson Anna , Aitken Sarah , Allinson Kieren , Stewart Grant , McDermott Ultan , Beddowes Emma , Maughan Tim , Ansorge Olaf , Campbell Peter , Roxburgh Patricia , Fraser Sioban , Blyth Kevin , Le Quesne John , Krebs Matthew , Blackhall Fiona , Summers Yvonne , Oliveira Pedro , Ortega-Franco Ana , Dive Caroline , Gomes Fabio , Carter Mat , Dransfield Jo , Thomas Anne , Fennell Dean , Shaw Jacqui , Wilson Claire , Marrone Domenic , Naidu Babu , Baijal Shobhit , Tanchel Bruce , Langman Gerald , Robinson Andrew , Collard Martin , Cockcroft Peter , Ferris Charlotte , Bancroft Hollie , Kerr Amy , Middleton Gary , Webb Joanne , Kadiri Salma , Colloby Peter , Olisemeke Bernard , Wilson Rodelaine , Shackleford Helen , Osman Aya , Tomlinson Ian , Jogai Sanjay , Holden Samantha , Fernandes Tania , McNeish Iain , Hampton Blanche , McKenzie Mairead , Hackshaw Allan , Sharp Abby , Chan Kitty , Farrelly Laura , Bridger Hayley , Leslie Rachel , Tookman Adrian , Swanton Charles , Jamal-Hanjani Mariam , Lise Stefano , Sandhu Shahneen , Attard Gerhardt 
Published: August 2023

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.