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

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Clear cell renal cell carcinoma (ccRCC) is a significant cancer.
• Known genetic variants (VHL, PBRM1, SETD2) are linked to ccRCC.
• The impact of structural variations (SVs) and 3D genome organization in ccRCC is not well understood.

Purpose of the Study:

• To comprehensively characterize the role of SVs and 3D genome architecture in ccRCC.
• To identify novel SV-associated oncogenic targets and understand their interplay with 3D genome.
• To develop a prognostic framework for ccRCC based on these findings.

Main Methods:

• Multi-omics analysis to identify SVs and their genomic impact.
• 3D genome architecture analysis to reveal reorganization during ccRCC progression.
• Experimental validation of identified enhancer hijacking events.

Main Results:

• Novel SV-associated oncogenic targets were identified in ccRCC.
• Multidimensional 3D genome reorganization was observed during ccRCC progression.
• An unrecognized pathogenic enhancer hijacking event activating SEMA5B was discovered and validated.
• A machine learning-based prognostic framework using enhancer hijacking signatures was developed.

Conclusions:

• Structural variations and 3D genome reorganization collectively drive ccRCC oncogenesis.
• Findings provide a valuable resource for ccRCC research.
• The developed prognostic tool offers clinical applicability for ccRCC patient outcomes.