Cis-regulatory Element Hijacking by Structural Variants Overshadows Higher-Order Topological Changes in Prostate Cancer

Abstract

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.

H3K27ac HiChIP in prostate cell lines identifies risk genes for prostate cancer susceptibility

“…Recent data suggest that the majority (>80%) of common loops identified in primary benign prostate tissue and prostate tumors are overlapping, further indicating that de novo looping is not a major driver of transcriptional differences in differentiated tissue. 41 While the current data suggest that loops are relatively static, more experiments across a wider variety of conditions are needed to understand the generalizability of these observations. We utilized high-resolution H3K27ac-HiChIP data in the LNCaP prostate cancer cell line, the most widely used in vitro model of prostate cancer, to identify links between target genes and PrCa risk loci.…”

Chromosome compartmentalization alterations in prostate cancer cell lines model disease progression

“…Recent efforts ( Hawley et al, 2021 Preprint ) have characterized 3D genomic profiles in prostate tumor cohorts. These studies recapitulate our findings that the 3D genome organization between malignant and benign prostate tissues remains largely consistent.…”

Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

“…The most significantly associated ARBS (p = 2 x 10 -8 ) was in an intergenic region that physically interacts with the FGFR2 promoter in LNCaP cells (Fig. 7E) and benign prostate tissue 75 . FGFR2 encodes a receptor highly expressed in prostate stroma that is implicated in the development of BPH 76 .…”