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A river model to map convergent cancer evolution and guide therapy in RCC

Abstract

Intratumoural heterogeneity in clear cell renal cell carcinoma (ccRCC) complicates identification and validation of biomarkers and thwarts attempts to improve precision medicine. Efforts to depict intratumoural heterogeneity and to pinpoint strategies for disease control resulted in the creation of the trunk–branch model of mutational cancer evolution, which emphasizes targeting trunk mutations. However, most patients with ccRCC receiving current therapeutics that target these mutations, such as inhibitors of vascular endothelial growth factors, eventually develop resistance. A novel paradigm might improve depiction of cancer evolution and advise therapeutic selection: the river model is based on findings from multiregion sequencing in samples from exceptional responders to mTOR inhibitors. The accumulating data on genotypic and phenotypic convergence in renal cell carcinoma and other malignancies can be used to examine how a mutable river model might best describe clinically significant phenotype-convergent events that could guide effective cancer control. This model originates from studying exceptional responders and its generalizability awaits validation.

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Figure 1: Mutations demonstrating convergent evolution.
Figure 2: The braided river model of convergent cancer evolution.

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Acknowledgements

We thank our patients for donating their tumours and the team members of the Memorial Sloan Kettering Cancer Center Translational Kidney Cancer Research Program for the advancement of kidney cancer research. The originally submitted illustrations were provided by Ms Wenjing Wu. This work is supported by the J. Randall & Kathleen L. MacDonald Kidney Cancer Research Fund.

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Correspondence to James J. Hsieh.

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Wei, E., Hsieh, J. A river model to map convergent cancer evolution and guide therapy in RCC. Nat Rev Urol 12, 706–712 (2015). https://doi.org/10.1038/nrurol.2015.260

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