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arXiv · 2503.13189

Causes of evolutionary divergence in prostate cancer

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

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Emre Esenturk, Atef Sahli, Valeriia Haberland, Aleksandra Ziuboniewicz, Christopher Wirth, G. Steven Bova, Robert G Bristow, Mark N Brook, Benedikt Brors, Adam Butler, Géraldine Cancel-Tassin, Kevin CL Cheng, Colin S Cooper, Niall M Corcoran, Olivier Cussenot, Ros A Eeles, Francesco Favero, Clarissa Gerhauser, Abraham Gihawi, Etsehiwot G Girma, Vincent J Gnanapragasam, Andreas J Gruber, Anis Hamid, Vanessa M Hayes, Housheng Hansen He, Christopher M Hovens, Eddie Luidy Imada, G. Maria Jakobsdottir, Chol-hee Jung, Francesca Khani, Zsofia Kote-Jarai, Philippe Lamy, Gregory Leeman, Massimo Loda, Pavlo Lutsik, Luigi Marchionni, Ramyar Molania, Anthony T Papenfuss, Diogo Pellegrina, Bernard Pope, Lucio R Queiroz, Tobias Rausch, Jüri Reimand, Brian Robinson, Thorsten Schlomm, Karina D Sørensen, Sebastian Uhrig, Joachim Weischenfeldt, Yaobo Xu, Takafumi N Yamaguchi, Claudio Zanettini, Andy G Lynch, David C Wedge, Daniel S Brewer, Dan J Woodcock. 2025-03-17. Causes of evolutionary divergence in prostate cancer. https://arxiv.org/abs/2503.13189

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