Structural variation drives enhancer hijacking via 3D genome disruption in ccRCC.

Clear cell renal cell carcinoma (ccRCC) is an aggressive malignancy associated with single-nucleotide variants in VHL, PBRM1, and SETD2. However, the role of structural variation (SV)-which have broader genomic impacts-and 3D genome architecture in ccRCC remains inadequately understood. Here, we reported a comprehensive molecular characterization. Through multi-omics analysis, we identify novel SV-associated oncogenic targets and reveal multidimensional 3D genome reorganization during ccRCC progression. We elucidate the dynamic interplay between SV and 3D chromatin architecture, demonstrating how structural rearrangements drive oncogenic dysregulation through 3D genome reorganization. Notably, an unrecognized pathogenic enhancer hijacking event is discovered and experimentally validated, leading to constitutive activation of the proto-oncogene SEMA5B. Furthermore, we developed a machine learning-based prognostic framework using enhancer hijacking signatures. Collectively, this work establishes a valuable resource for ccRCC research by elucidating how SVs and 3D genome reorganization collectively drive oncogenesis, and translates these findings into a clinically applicable prognostic tool.