Circulating Cell-Free DNA in Renal Cell Carcinoma: The New Era of Precision Medicine

Simple Summary Early diagnosis of renal cell carcinoma (RCC) is challenging and typically incidental. Currently, several therapeutic strategies are used for the treatment; however, no established predictive biomarker has been established yet, and the optimal treatment choice and sequence of use remain unclear. Moreover, the recurrence occurs in about one-third of patients after tumor resection. Although several prognostic classification systems have been proposed, most of them showed only limited potential in recurrence prediction. Therefore, identifying simple, reliable, and easily accessible biomarkers to anticipate the diagnosis, effectively evaluate the risk of relapse, and predict the response to the therapeutic regimens is an unmet clinical need. Circulating cell-free DNA (cfDNA), released from cancer cells into the bloodstream, was shown to be a non-invasive, viable, inexpensive method to diagnose and monitor several solid malignancies, designed as a potential blood RCC biomarker. This review aims to summarize the state of the art of the current genetic and epigenetic techniques of plasma and serum cfDNA detection and outline the potential application of liquid biopsy in RCC. Tumor biopsy is still the gold standard for diagnosing and prognosis renal cell carcinoma (RCC). However, its invasiveness, costs, and inability to accurately picture tumor heterogeneity represent major limitations to this procedure. Analysis of circulating cell-free DNA (cfDNA) is a non-invasive cost-effective technique that has the potential to ease cancer detection and prognosis. In particular, a growing body of evidence suggests that cfDNA could be a complementary tool to identify and prognosticate RCC while providing contemporary mutational profiling of the tumor. Further, recent research highlighted the role of cfDNA methylation profiling as a novel method for cancer detection and tissue-origin identification. This review synthesizes current knowledge on the diagnostic, prognostic, and predictive applications of cfDNA in RCC, with a specific focus on the potential role of cell-free methylated DNA (cfMeDNA).