Diagnostic liquid biopsy biomarkers in renal cell cancer

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. In this Review, the authors provide an overview of currently available diagnostic liquid biopsy biomarkers for renal cell carcinoma, comparing clinical potential and limitations of the three most promising liquid biomarkers: circulating tumour cells, extracellular vesicles and cell-free DNA. 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.