Abstract A052: Chromatin conformational changes in prostate cancer progression

Abstract

Abstract Introduction. Prostate cancer (PCa) is the second most common cancer in men worldwide. Globally, it is among the top three leading causes of cancer-related mortality in men. Although many patients carry an indolent form of PCa, a subset of patients develops the aggressive form of PCa which is often treated by androgen depletion therapy. Despite treatment, the disease, in a subgroup of patients, progresses to develop castration resistant prostate cancer (CRPC). Despite the ongoing efforts, the underlying progression mechanisms are not yet fully understood. A more comprehensive understanding may offer translational benefits. Thus, using patient sample-derived high-throughput sequencing data from multiple epigenetic data layers together with expression levels of genes and proteins, we aim to uncover aberrant regulatory mechanisms and their role in PCa progression. Methods. We characterize the PCa progression-related conformational chromatin changes by applying Hi-C to clinical samples from a cohort of 18 patients, divided into three evenly-sized groups: benign prostatic hyperplasia (BPH), untreated prostate cancer (PC), and CRPC. We further characterize our findings by integrating chromatin accessibility, DNA methylation, gene and protein expression data from matching samples. Results. Looking at active and inactive (A/B) compartments, as inferred by Hi-C data, we observe that they are in high agreement across the sample groups. Integrating these A/B compartments with DNA-methylation data, we observe an elevated and decreased genome-wide methylation pattern respectively. Looking at topologically associating domain (TAD) boundaries, we observe a high agreement across sample groups as 70% of the TAD boundaries are shared by all groups. Focusing in on the chromatin loops, we observe more heterogeneity compared to the overall chromatin conformation as 38% of the loops are sample-specific. Detecting differential loops followed by their integration with gene expression data for genes overlapping the differential loop anchors, we observe an association between differential loop strength and gene expression as PC develops. Further integration of the differential loops with accessible chromatin regions, as inferred by ATAC-seq data, gene expression, and publicly available transcription factor (TF) binding data, we observe that distal enhancers of up-regulated genes in PC are enriched for PCa-relevant TFs such as FOXA1, HOXB13, and GATA2, but we see no enrichment for up-regulated loops in PC. In CRPC, these same TFs are enriched for up-regulated loops, but this does not seem to affect the gene expression. Conclusion. Our results suggest while PC samples undergo a more uniform set of chromatin conformational changes, CRPC samples indicate elevated heterogeneity in their acquired conformational changes potentially contributing to a more aberrant disease progression trajectory. Citation Format: Tuomo Virtanen, Ebrahim Afyounian, Riikka Nurminen, Teuvo Tammela, Alfonso Urbanucci, Juha Kesseli, Kirsi Rautajoki, Tapio Visakorpi, Matti Nykter. Chromatin conformational changes in prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A052.