Integrated analyses highlight interactions between the 3D-genome and DNA, RNA, and epigenomic alterations in metastatic prostate cancer

ABSTRACT: Advances in next generation sequencing have expanded our understanding of the molecular drivers of prostate cancer progression from curable androgen-sensitive disease to metastatic castration-resistant prostate cancer (mCRPC). The focus to date has been on the linear genome, but the impact of variations in the 3D structure of the genome on tumor development and progression has been increasingly recognized. However, studies of human cancer tissues, and especially solid tumors, are extremely limited. Herein, we performed the first integrated low-input deep Hi-C sequencing with matched whole-genome sequencing, whole-genome bisulfite sequencing, 5hmC-seq, and RNA-seq across a cohort of 80 mCRPC biopsy samples. We identify dramatic differences in gene expression, 5mC and 5hmC methylation, and mutation rate between A/B (open/closed) chromatin compartments, as well as a novel association between structural variation and A compartments. By probing the 3D genome, we identify samples with depleted regional chromatin contacts at the Androgen Receptor locus linked to extra-chromosomal circular DNA (ecDNA) and worse response to Androgen Signaling Inhibitors (ASIs). We also identify two never-before described topological subtypes with broad vs. narrow Topologically Associated Domain (TAD) structures, which are associated with stark differences in methylation structure, gene expression, and prognosis. Structural Variants (SVs) can be identified using Hi-C, but in the first such observation in clinical tumor samples, we demonstrate that DNA interactions may contribute and predispose to SV formation, exemplified by the recurrent TMPRSS2-ERG fusion. This large and comprehensive effort provides unprecedented insights into how the 3D genome interacts with the genomic and epigenomic drivers of cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249494 | GEO | 2024/05/16

REPOSITORIES: GEO