Abstract 2033: Rearrangement of the 3D genome structure in prostate cancer is a potential mechanism for disease exacerbation and classifies cancers according to progression
Authors: Martin Rebeca San , Das Priyojit , Marques Renata Dos Reis , McCord Rachel P. 
Published: July 2021

Prostate cancer (PCa) aggressiveness and propensity to metastasize can be influenced by gene expression patterns, genomic aberrations, and overall cellular and nuclear morphology. The 3D folding of chromosomes into loops, domains, and territories as they are packaged into the nucleus plays a key role in all of these processes, affecting proper gene regulation, DNA replication and repair, and nuclear physical properties. However, while nuclear atypia has long been used as a marker of PCa progression, little is known about what changes in 3D genome interactions occur or how these may influence cancer-promoting gene expression profiles or the nuclear malleability necessary for cancer cells to metastasize. Thus, we set out to characterize the role of the 3D genome changes in PCa, analyzing changes in the 3D genome structure of cell lines that model the continuum of disease. Using chromosome conformation capture (Hi-C) we have conducted a systematic comparison of the 3D genome structure of a normal epithelium model cell line (RWPE) to that of adenocarcinoma (LNCaP), bone metastatic (VCaP, PC3, 22RV1, LNCaP-C42B, MDaPCa2a and MDAPCa2b), and atypical metastasis (Brain - DU145) lines. Our study has shown that the open/closed chromatin compartmentalization identity (A vs B compartment) changes with progression. We have characterized a cohort of 316 genes whose compartmentalization changes from the B to the A compartment, suggesting that those genes become poised for transcription. These include androgen receptor, WNT5A and CDK14, as well as genes located in proximity to TMPRSS2, such as BACE2. The positive correlation between switches of compartmentalization identity and transcription activation has been confirmed by microarray. Of these B/A switch genes, 256 are grouped in 48 proximal clusters. We have also identified 84 genes whose compartments switch from the A to B compartment, suggesting a genomic rearrangement that could result in silencing. Such is the case of certain cadherins, annexins and mediators of inflammation. Of these, 64 are grouped in 16 clusters. Finally, we have observed that compartmentalization changes in chromosome 21 are exacerbated with progression and may explain, in part, the genesis of the TMPRSS2-ERG translocation; one of the main drivers of prostate cancer, present in 40% - 80% of prostate cancer patients. Interestingly, changes in gene transcription are also accompanied by changes in the structure, size, and boundaries of the topologically associating domains (TADs) surrounding the loci of interest, suggesting that 3D genome structure plays a role in the activation of alternate pathways for proliferation and survival.

Citation Format: Rebeca San Martin, Priyojit Das, Renata Dos Reis Marques, Rachel P. McCord. Rearrangement of the 3D genome structure in prostate cancer is a potential mechanism for disease exacerbation and classifies cancers according to progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2033.