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. Clear cell kidney cancer is the most common type of kidney cancer. In most patients, a small piece of DNA is missing. This piece contains several genes that normally control how DNA is read and used. These genes include VHL, PBRM1, SETD2, and BAP1. When these genes are lost, the cell’s instruction manual becomes disordered. This review explains how these changes affect kidney cancer. These changes are often called epigenetic changes. They do not change the DNA code itself. Instead, they add or remove chemical marks on DNA and proteins. These marks turn genes on or off. In this cancer, these marks are disturbed in many ways. This includes changes in chemical marks, small RNA molecules, and cell waste products. Together, these changes help cancer cells grow, spread, and resist treatment. Doctors can use these changes. They can be found in urine or blood with simple tests. These tests can help find cancer early and predict how well a patient will do. These changes also show weaknesses in cancer cells. Drugs can target these weaknesses. For example, cancers with BAP1 loss may respond to drugs called PARP inhibitors. Cancers with SETD2 loss may respond to drugs called ATR or CHK1 inhibitors. Cancers with PBRM1 loss may respond to immunotherapy or drugs called EZH2 inhibitors. In the next 5 to 10 years, new tools may bring these findings into routine care. These tools include ways to study single cells and their locations, blood and urine tests, and combining treatments. This review aims to help patients, doctors, and the public understand how epigenetic changes drive this cancer. It also explains how these changes can be used for better diagnosis and treatment.