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  • Review Article
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Diagnostic liquid biopsy biomarkers in renal cell cancer

Nature Reviews Urology volume 21, pages 133–157 (2024)Cite this article

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Abstract

The clinical presentation of renal cell cancer (RCC) is shifting towards incidental and early detection, creating new challenges in RCC diagnosis. Overtreatment might be reduced with the development of new diagnostic biomarkers to distinguish benign from malignant small renal masses (SRMs). Differently from tissue biopsies, liquid biopsies are obtained from a patient’s blood or urine and, therefore, are minimally invasive and suitable for longitudinal monitoring. The most promising types of liquid biopsy biomarkers for RCC diagnosis are circulating tumour cells, extracellular vesicles (EVs) and cell-free DNA. Circulating tumour cell assays have the highest specificity, with low processing time and costs. However, the biological characteristics and low sensitivity limit the use of these markers in SRM diagnostics. Cell-free DNA might complement the diagnosis of high-volume RCC, but the potential for clinical application in SRMs is limited. EVs have the highest biological abundance and the highest sensitivity in identifying low-volume disease; moreover, the molecular characteristics of these markers make EVs suitable for multiple analytical applications. Thus, currently, EV assays have the greatest potential for diagnostic application in RCC (including identification of SRMs). All these liquid biomarkers have potential in clinical practice, pending validation studies. Biomarker implementation will be needed to also improve characterization of RCC subtypes. Last, diagnostic biomarkers might be extended to prognostic or predictive applications.

Key points

  • The shift towards early renal cell cancer (RCC) diagnosis comes with a demand for novel biomarkers to face diagnostic challenges in the identification of small renal masses (SRMs) and characterization of RCC subtypes.

  • Liquid biopsy is less invasive than tumour biopsy, but, to date, no liquid biopsy biomarkers have been clinically approved for RCC diagnosis.

  • Circulating tumour cells (CTCs) seem less suitable than extracellular vesicles (EVs) for cancer detection in SRMs, owing to low epithelial cell adhesion molecule (EPCAM) expression in RCC and low biological abundance of CTCs in early stages of the disease.

  • Cell-free DNA seems to be more promising as a predictive biomarker of response to systemic metastatic RCC therapies than as a diagnostic biomarker owing to the low biological abundance of this marker in RCC, especially in SRMs.

  • EVs have the highest potential as diagnostic biomarkers in RCC, especially SRMs.

  • Further standardization and simplification are still required in all experimental RCC biomarker assays before liquid biopsy can be applied in clinical practice.

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Fig. 1: Circulating tumour cells, cell-free DNA and extracellular vesicles enter the blood circulation.
Fig. 2: Parameters relevant for clinical implementation of renal cell carcinoma biomarkers in liquid biopsy samples.

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Acknowledgements

R.C.Z. discloses support for the research of this work from the Stichting Cure for Cancer Foundation, Amsterdam, the Netherlands. K.J.P. discloses support for the research of this work from the NCI [grant numbers U54CA143803, CA163124, CA093900 and CA143055] and the Prostate Cancer Foundation.

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Authors and Affiliations

  1. Department of Urology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Richard C. Zieren, Patricia J. Zondervan & Theo M. de Reijke

  2. The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Richard C. Zieren & Kenneth J. Pienta

  3. Specialist Centre for Kidney Cancer, Royal Free Hospital, London, United Kingdom

    Axel Bex

  4. Division of Surgery and Interventional Science, University College London, London, United Kingdom

    Axel Bex

  5. The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Axel Bex

  6. Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Adriaan D. Bins

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R.C.Z. researched data for the article. All authors contributed substantially to discussion of the content. R.C.Z. and A.D.B. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Zieren, R.C., Zondervan, P.J., Pienta, K.J. et al. Diagnostic liquid biopsy biomarkers in renal cell cancer. Nat Rev Urol 21, 133–157 (2024). https://doi.org/10.1038/s41585-023-00818-y

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