Abstract 4720: Chromatin conformation alterations in prostate cancer progression and formation of castration resistance

Introduction: Prostate cancer (PC) is the most common cancer in men and second in cancer related deaths. Aggressive prostate cancer is typically treated with androgen depletion therapy which often results in the formation of castration resistant prostate cancer (CRPC). Androgen receptor (AR) is a transcription factor that regulates hundreds of target genes and is responsible for the differentiation and function of normal prostate epithelial cells. In addition to AR, multiple other TFs that bind to distal enhancers have been implicated in PC, such as FOXA1, MYC and HOXB13. Understanding the role of these distal regulators is paramount in PC. Methods: To study the changes in chromatin conformation in prostate cancer progression, we have sequenced clinical benign prostatic hyperplasia (BPH), PC and CRPC samples using Hi-C sequencing. From each group 6 samples were sequenced with a total of 18 samples in the cohort. In addition, we have combined a multi omics cohort consisting of chromatin accessibility, transcriptome and methylome sequencing data from matching samples. Together these data types allow us to map out the regulatory networks in PC and CRPC by probing the distal active regulatory sites and their interactions. To account for artifacts caused by genomic aberrations in cancer samples we have established a pipeline for normalizing these effects in HiC-data. Results: Overall topologically associated domains (TADs) and A/B-compartments remain stable between the groups. However, local changes of compartments in loci of key genes, such as AKR1C3 and FOXA1 correlate with their gene expression. We detect differential loops between sample groups and these changes are associated with gene expression alterations in PCs. Distal enhancers of PC up-regulated genes are enriched for FOXA1 and HOXB13. Interestingly, up-regulated loops in CRPC are enriched for FOXA1 and HOXB13, while no systematic effect on gene expression is seen on a genome wide scale, apart from genes such as AR and CENPE whose expression correlates strongly with their association to distal enhancers. We also detect enhancer hijacking events in driver genes. One example is the recurrent ETV1-MIPOL1 fusion, where promoter of ETV1 forms contacts with FOXA1 enhancer regions. Conclusions: Alterations in loop structures are strongly associated with regulatory programs that have been previously implicated in PC, including regulation by FOXA1, HOXB13 and other transcription factors. This highlights the i