Cis-Regulatory Element Hijacking by Structural Variants Overshadows Topological Changes in Primary Prostate Cancer

Prostate cancer is a heterogeneous disease whose progression is linked to genome instability 1. Despite large-scale tumour sequencing efforts, the impact of mutations on the genetic architecture in cancer remains ill-defined due to limited integration of genomics data across dimensions 2. We addressed this limitation by assessing the impact of structural variants on the chromatin states and the three-dimensional organization across benign and malignant primary prostate genomes. We find high concordance in the three-dimensional genome organization between malignant and benign prostate tissues, arguing for constraints to the three-dimensional genome of prostate tumours. Moreover, we identify structural variants as effectors of changes to focal chromatin interactions, guiding cis-regulatory element hijacking 2,3 that imposes opposing expression changes on genes found at antipodes of a rearrangement. This leads to the repression of tumour suppressor gene expression and up-regulation of oncogenes, such as at the TMPRSS2-ERG and PMEPA1-ZNF156 loci. Collectively, our results argue that cis-regulatory element hijacking by structural variants overshadows large-scale topological changes to alter gene regulation and promote oncogenesis.