Abstract
Metastatic prostate cancer remains an incurable lethal disease. Studies indicate that prostate cancer accumulates genomic changes during disease progression and displays the highest levels of chromosomal instability (CIN) across all types of metastatic tumours. CIN, which refers to ongoing chromosomal DNA gain or loss during mitosis, and derived aneuploidy, are known to be associated with increased tumour heterogeneity, metastasis and therapy resistance in many tumour types. Paradoxically, high CIN levels are also proposed to be detrimental to tumour cell survival, suggesting that cancer cells must develop adaptive mechanisms to ensure their survival. In the context of prostate cancer, studies indicate that CIN has a key role in disease progression and might also offer a therapeutic vulnerability that can be pharmacologically targeted. Thus, a comprehensive evaluation of the causes and consequences of CIN in prostate cancer, its contribution to aggressive advanced disease and a better understanding of the acquired CIN tolerance mechanisms can translate into new tumour classifications, biomarker development and therapeutic strategies.
Key points
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Metastatic prostate cancer displays high levels of chromosomal instability (CIN); however, the causal mechanisms and cellular and tumoural consequences of harbouring highly complex genomes are not completely understood.
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High-CIN prostate cancer adapts to ongoing chromosomal aberration accumulation developing unique functional dependencies.
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CIN adaptation vulnerabilities can be exploited to therapeutically target prostate cancer.
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Evaluation of CIN levels in tumour samples and liquid biopsies might enable stratification of patient prognosis and help to personalize treatment decisions.
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Acknowledgements
V.R.-B. is funded by NIH-NCI R01 CA237398. J.D.-D. is funded by NIH-NCI R01 CA207311. Both V.R.-B. and J.D.-D. are supported by the Mayo Clinic Foundation. The authors thank E. Gerner for his continued philanthropic support.
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Carceles-Cordon, M., Orme, J.J., Domingo-Domenech, J. et al. The yin and yang of chromosomal instability in prostate cancer. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-023-00845-9
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DOI: https://doi.org/10.1038/s41585-023-00845-9
