Multi-omics insights into tumor grade progression in clear cell renal cell carcinoma: from molecular mechanisms to precision therapeutics (opens in new tab)

Clear cell renal cell carcinoma (ccRCC) can transition from indolent, low-grade lesions to high-grade, lethal disease through a layered cascade of genomic, epigenomic, metabolic, and immune remodeling. The initiating event in ∼90% of ccRCC is loss of chromosome 3p, enabling biallelic inactivation of VHL and frequent co-loss of chromatin regulators PBRM1, BAP1, and SETD2. The order and combination of genetic alterations shape distinct evolutionary trajectories in ccRCC. PBRM1 loss, observed in...