Tumor architecture and emergence of strong genetic alterations are bottlenecks for clonal evolution in primary prostate cancer.

Cell systems Pub Date : 2024-11-20 Epub Date: 2024-11-13 DOI:10.1016/j.cels.2024.10.005
Florian Kreten, Reinhard Büttner, Martin Peifer, Christian Harder, Axel M Hillmer, Nima Abedpour, Anton Bovier, Yuri Tolkach
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Abstract

Prostate cancer (PCA) exhibits high levels of intratumoral heterogeneity. In this study, we developed a mathematical model to study the growth and genetic evolution of PCA. We explored the possible evolutionary patterns and demonstrated that tumor architecture represents a major bottleneck for divergent clonal evolution. Early consecutive acquisition of strong genetic alterations serves as a proxy for the formation of aggressive tumors. A limited number of clonal hierarchy patterns were identified. A biopsy study of synthetic tumors shows complex spatial intermixing of clones and delineates the importance of biopsy extent. Deep whole-exome multiregional next-generation DNA sequencing of the primary tumors from five patients was performed to validate the results, supporting our main findings from mathematical modeling. In conclusion, our model provides qualitatively realistic predictions of PCA genomic evolution, closely aligned with the evidence available from patient samples. We share the code of the model for further studies. A record of this paper's transparent peer review process is included in the supplemental information.

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肿瘤结构和强基因改变的出现是原发性前列腺癌克隆进化的瓶颈。
前列腺癌(PCA)表现出高度的瘤内异质性。在这项研究中,我们建立了一个数学模型来研究 PCA 的生长和遗传进化。我们探索了可能的进化模式,并证明肿瘤结构是分化克隆进化的主要瓶颈。早期连续获得强基因改变可代表侵袭性肿瘤的形成。研究发现了数量有限的克隆分级模式。对合成肿瘤的活检研究显示了复杂的克隆空间混杂,并划定了活检范围的重要性。对五名患者的原发肿瘤进行了深度全外显子组多区域下一代 DNA 测序,以验证结果,从而支持我们从数学建模中得出的主要结论。总之,我们的模型对 PCA 基因组进化做出了定性的现实预测,与患者样本中的证据密切吻合。我们分享了该模型的代码,以供进一步研究。本文透明的同行评审过程记录见补充信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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