Clinical Practice and Prognostic Molecular Biomarkers in Clear Cell Renal Cell Carcinoma: Latest Advancements

Renal cell carcinoma (RCC) is a common urologic cancer that accounts for approximately 3% of all human malignancies. It is divided into different histotypes among which the clear cell renal cell carcinoma (ccRCC) is the most frequent and severe. Many signaling pathways are dysregulated in ccRCC including VHL/HIF axis, mTOR-mediated signals, p53 dysfunction, autophagy modulation and programmed cell death inhibition. Currently, the recommended first line therapy consists of immune checkpoint inhibitors (ICIs) in combination with each other or with tyrosine kinase inhibitors (TKIs). These combination therapies have improved overall survival (OS) and the quality of life of patients with ccRCC. Nevertheless, metastatic renal carcinoma (mRCC) is hard to cure and the life expectancy remains relatively low. Notably, patients with mRCC may show different disease outcomes with survival ranging from few weeks to several years indicating that this pathology is very heterogeneous, likely due to different molecular and pathophysiological features. Therefore, the research, development and clinical application of informative biomarkers for high and low risk stratification of patients with ccRCC is crucial to select the best therapeutic option. In this review, we discuss the clinical parameters of RCC, surgery and systemic therapy as well as the putative prognostic molecular biomarkers also useful for cytoreductive nephrectomy. Many biomarkers belong to signaling pathways such as VHL/HIF, ERK/MAPK, mTOR/Akt or biological processes including autophagy, anoikis, cuproptosis, disulfidptosis and ferroptosis that are altered in ccRCC. The transfer in clinical practice of precise biomarkers able to predict prognosis may help clinicians in the management of patients with ccRCC.