Causes of evolutionary divergence in prostate cancer

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Esenturk, Emre, Sahli, Atef, Haberland, Valeriia, Ziuboniewicz, Aleksandra, Wirth, Christopher, Bova, G. Steven, Bristow, Robert G., Brook, Mark N., Brors, Benedikt, Butler, Adam, Cancel-Tassin, Géraldine, Cheng, Kevin C. L., Cooper, Colin S., Corcoran, Niall M., Cussenot, Olivier, Eeles, Ros A., Favero, Francesco, Gerhauser, Clarissa, Gihawi, Abraham, Girma, Etsehiwot G., Gnanapragasam, Vincent J., Gruber, Andreas J., Hamid, Anis, Hayes, Vanessa M., He, Housheng Hansen, Hovens, Christopher M., Imada, Eddie Luidy, Jakobsdottir, G. Maria, Jung, Chol-Hee, Khani, Francesca, Kote-Jarai, Zsofia, Lamy, Philippe, Leeman, Gregory, Loda, Massimo, Lutsik, Pavlo, Marchionni, Luigi, Molania, Ramyar, Papenfuss, Anthony T., Pellegrina, Diogo, Pope, Bernard, Queiroz, Lucio R., Rausch, Tobias, Reimand, Jüri, Robinson, Brian, Schlomm, Thorsten, Sørensen, Karina D., Uhrig, Sebastian, Weischenfeldt, Joachim, Xu, Yaobo, Yamaguchi, Takafumi N., Zanettini, Claudio, Lynch, Andy G., Wedge, David C., Brewer, Daniel S. and Woodcock, Dan J. (2025) Causes of evolutionary divergence in prostate cancer.

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Abstract

Cancer progression involves the sequential accumulation of genetic alterations that cumulatively shape the tumour phenotype. In prostate cancer, tumours can follow divergent evolutionary trajectories that lead to distinct subtypes, but the causes of this divergence remain unclear. While causal inference could elucidate the factors involved, conventional methods are unsuitable due to the possibility of unobserved confounders and ambiguity in the direction of causality. Here, we propose a method that circumvents these issues and apply it to genomic data from 829 prostate cancer patients. We identify several genetic alterations that drive divergence as well as others that prevent this transition, locking tumours into one trajectory. Further analysis reveals that these genetic alterations may cause each other, implying a positive-feedback loop that accelerates divergence. Our findings provide insights into how cancer subtypes emerge and offer a foundation for genomic surveillance strategies aimed at monitoring the progression of prostate cancer.

Item Type:	Article
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Related URLs:	http://arxiv.org/pdf/2503.13189v1
Depositing User:	LivePure Connector
Date Deposited:	04 Jun 2025 14:30
Last Modified:	04 Jun 2025 14:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99395
DOI:

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