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

2023; Nature Portfolio; Volume: 14; Issue: 1 Linguagem: Inglês

10.1038/s41467-023-40315-9

2041-1723

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, Simone Zaccaria, Sonya Hessey, Kai‐Keen Shiu, John Bridgewater, Daniel Hochhauser, Martin Förster, Siow Ming Lee, Tanya Ahmad, Dionysis Papadatos-Pastos, Sam M. Janes, Peter Van Loo, Katey S.S. Enfield, Nicholas McGranahan, Ariana Huebner, Sergio A. Quezada, Stephan Beck, Peter J. Parker, Tariq Enver, Robert E. Hynds, David R. Pearce, Mary Falzon, Ian Proctor, Ron Sinclair, Chi-wah Lok, Zoe Rhodes, David A. Moore, Teresa Marafioti, Miriam Mitchison, Peter Ellery, Monica Sivakumar, Mark Linch, Sebastian Brandner, Andrew Rowan, Crispin T. Hiley, Selvaraju Veeriah, Heather M. Shaw, Cristina Naceur‐Lombardelli, Antonia Toncheva, Paulina Prymas, Thomas B.K. Watkins, Chris Bailey, Carlos Martínez‐Ruiz, Kevin Litchfield, Maise Al-Bakir, Nnenna Kanu, Sophia Ward, Emilia L. Lim, James L. Reading, Benny Chain, Tom Watkins, Melek Akay, Adrienne M. Flanagan, Dhruva Biswas, Oriol Pich, Michelle Dietzen, Clare Puttick, Emma Colliver, Alastair Magness, Mihaela Angelova, James R. Black, Olivia Lucas, William Hill, Wing-Kin Liu, Alexander M. Frankell, Neil Magno, Foteini Athanasopoulou, Roberto Salgado, Claudia Lee, Kristiana Grigoriadis, Othman Al‐Sawaf, Takahiro Karasaki, Abigail Bunkum, Imran Noorani, Sarah Benafif, Vittorio Barbè, Supreet Kaur Bola, Gianmarco Leone, Constantine Alifrangis, Ursula McGovern, Kerstin Thol, Samuel Gamble, Seng Kuong Anakin Ung, Teerapon Sahwangarrom, Claudia Peinador Marin, Sophia Wong, Piotr Pawlik, Jie Min Lam, Corentin Richard, Roberto Vendramin, Krijn K. Dijkstra, Jayant K. Rane, Jérôme Nicod, Angela Dwornik, Kerry Bowles, Rija Zaidi, Faye Gishen, Paddy Stone, Caroline Stirling, Samra Turajlic, James Larkin, Lisa Pickering, Andrew J.S. Furness, Kate Young, Will Drake, Kim Edmonds, Nikki Hunter, Mary Mangwende, Karla Pearce, Lauren Grostate, Lewis Au, Lavinia Spain, Scott T.C. Shepherd, Haixi Yan, Benjamin Shum, Zayd Tippu, Brian Hanley, Charlotte Spencer, Max Emmerich, Camille L. Gérard, Andreas M. Schmitt, Lyra Del Rosario, Eleanor Carlyle, Charlotte B. Lewis, Lucy Holt, Analyn Lucanas, Molly O’Flaherty, Steve Hazell, Hardeep Singh Mudhar, Christina Messiou, Arash Latifoltojar, Annika Fendler, Fiona Byrne, Husayn Ahmed Pallikonda, Irene Lobón, Alexander Coulton, Anne-Laure Cattin, Daqi Deng, Hugang Feng, Andew Rowan, Nadia Yousaf, Sanjay Popat, Olivia Curtis, Charlotte Milner-Watts, Gordon Stamp, Emma Nye, Aida Murra, Justine Korteweg, Denise Kelly, Lauren Terry, Jennifer Biano, Kema Peat, Kayleigh Kelly, Charlotte Grieco, Mo Linh Le, Paolo D. d’Arienzo, Emma Turay, Peter Hill, Debra H. Josephs, Sheeba Irshad, James Spicer, Ula Mahadeva, Anna Green, Ruby Stewart, Natasha Wright, Georgina Pulman, Ruxandra Mitu, Sherene Phillips-Boyd, Deborah Enting, Sarah Rudman, Sharmistha Ghosh, Eleni Karapanagiotou, Elias Pintus, Andrew Tutt, Sarah Howlett, James D. Brenton, Carlos Caldas, Rebecca C. Fitzgerald, Merche Jimenez-Linan, Elena Provenzano, Alison D. Cluroe, Anna Paterson, Sarah J. Aitken, Kieren Allinson, Grant D. Stewart, Ultan McDermott, Emma Beddowes, Tim Maughan, Olaf Ansorge, Peter J. Campbell, Patricia Roxburgh, Sioban Fraser, Kevin Blyth, John Le Quesne, Matthew Krebs, Fiona Blackhall, Yvonne Summers, Pedro Oliveira, Ana Ortega-Franco, Caroline Dive, Fábio Gomes, Mat Carter, Jo Dransfield, Anne Thomas, Dean A. Fennell, Jacqui Shaw, Claire Wilson, Domenic Marrone, Babu Naidu, Shobhit Baijal, Bruce Tanchel, Gerald Langman, Andrew Robinson, Martin Collard, Peter Cockcroft, Charlotte Ferris, Hollie Bancroft, Amy Kerr, Gary Middleton, Joanne Webb, Salma Kadiri, Peter Colloby, Bernard Olisemeke, Rodelaine Wilson, Helen Shackleford, Aya Osman, Ian Tomlinson, Sanjay Jogai, Samantha K. Holden, Tânia Rita Moreno de Oliveira Fernandes, Iain A. McNeish, Blanche Hampton, Mairead McKenzie, Allan Hackshaw, Abby Sharp, Kitty S. Chan, Laura Farrelly, Hayley Bridger, Rachel Leslie, Adrian Tookman, Charles Swanton, Mariam Jamal‐Hanjani, Stefano Lise, Shahneen Sandhu, Gerhardt Attard,

Molecular Biology Techniques and Applications

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.