This study addresses to what extent somatic structural variants in cancer are formed by pre-existing genomic contacts and alter 3D genome architecture and affect nearby gene expression

Structural variants (SVs) are known to be influenced by the local chromatin state and the 3D chromatin architecture. Studies relating SVs to chromatin organization in cancer have primarily been conducted retrospectively, years to decades after SV occurrence, complicating their analysis. Here, we apply Hi-C to study chromatin organization before and after catastrophic SV induction in human cultured cells. We assemble derivative chromosomes following massive complex rearrangements, which we used to study the sources of SV formation and their consequences on gene regulation. We observe an action-reaction interplay whereby the 3D chromatin architecture directly impacts on the location and formation of SVs. In turn, the SVs reshape the chromatin organization to alter the local topologies, replication timing and gene regulation in cis. We show that genomic compartments and replication timing are important determinants for juxtaposing distant loci to form SVs across 30 different cancer types with a pronounced abundance of SVs between early replicating regions in uterine cancer. We find that SVs frequently occur at 3D loop-anchors, cause compartment switching and changes in replication timing, and that this is a major source of SV-mediated effects on nearby gene expression changes.