Prostate Cancer Foundation Canada
Ontario Institute for Cancer Research funded by the Government of Ontario
Princess Margaret Cancer Foundation
Princess Margaret Cancer Centre Department of Surgical Oncology
Princess Margaret Cancer Centre Genetics and Epigenetic Program
University of Toronto Department of Surgery Division of Urology
Radiation Medicine Program Academic Enrichment Fund
Terry Fox Research Institute New Investigator Award
Canadian Institute of Health Research
New Investigator Award
Canadian Cancer Society Research Scientist Award
Cancer Society Impact Award
Investigator Award from the Ontario Institute for Cancer Research
Movember Rising Star Award from PCa Canada
ARTICLE ABSTRACTProstate cancer is a heterogeneous disease whose progression is linked to genome instability. However, the impact of this instability on the noncoding genome and its three-dimensional organization to aid progression is unclear. Using primary benign and tumor tissue, we find a high concordance in higher-order three-dimensional genome organization. This concordance argues for constraints to the topology of prostate tumor genomes. Nonetheless, we identified changes in focal chromatin interactions, typical of loops bridging noncoding cis-regulatory elements, and showed how structural variants can induce these changes to guide cis-regulatory element hijacking. Such events resulted in opposing differential expression of genes found at antipodes of rearrangements. Collectively, these results argue that changes to focal chromatin interactions, as opposed to higher-order genome organization, allow for aberrant gene regulation and are repeatedly mediated by structural variants in primary prostate cancer.
This work showcases how the noncoding genome can be hijacked by focal insults to its three-dimensional organization that contribute to prostate cancer oncogenesis.