Epigenetic dysregulation in Clear cell renal cell carcinoma: from mechanisms to precision medicine

Clear cell renal cell carcinoma (ccRCC) is a paradigm of epigenetic dysregulation. The characteristic loss of chromosome 3p leads to the inactivation of a constellation of pivotal epigenetic regulators, including PBRM1, SETD2, and BAP1, reshaping the epigenome across multiple layers. This review synthesizes the major epigenetic alterations in ccRCC, encompassing aberrations in chromatin structure, dysregulation of DNA and RNA methylation, deregulated noncoding RNAs, and the accumulation of oncometabolites. Collectively, these changes drive oncogene activation, tumor suppressor silencing, genomic instability, and metabolic reprogramming. We also evaluate the clinical potential of these epigenetic alterations. First, they can serve as noninvasive diagnostic and prognostic biomarkers, particularly through the analysis of DNA methylomes and exosomes in liquid biopsies. Second, these alterations enable a therapeutic strategy-epigenetic synthetic lethality-which exploits vulnerabilities induced by the loss of VHL, BAP1, SETD2, and PBRM1. Such vulnerabilities are selectively targetable by PARP, ATR, or EZH2 inhibitors, thereby offering a novel framework for precision medicine in ccRCC. Finally, we outline future research directions, including dissecting intra-tumoral epigenetic heterogeneity, defining functional epigenetic biomarkers, expanding next-generation epigenetic therapeutics, targeting the metabo-epigenetic circuitry, and rationally integrating epigenetic modulators with immunotherapies and HIF-2α inhibitors, aiming to translate epigenetic knowledge into improved clinical outcomes.