Abstract
Abstract Genomic material within the nucleus is folded into successive layers in order to package and organize the long string of linear DNA. This hierarchical level of folding is closely associated with transcriptional regulation and DNA replication. Genes within the same folding domain demonstrate similar expression and histone-modification profiles. Therefore, boundaries separating different domains have important roles in reinforcing the stability of these domain-wide features. Indeed, domain boundary disruptions in human genetic disorders or human cancers lead to misregulation of certain genes, due to de novo enhancer exposure to promoters. However, the frequency of boundary disruptions in human cancers, and whether there are recurrently affected boundaries in specific cancer types, remains unclear. Here, to understand effects and distributions of somatic structural variations (SVs) across TADs, we utilized 288,457 high-confidence somatic structural variations from 2658 tumor-normal pair high-coverage whole genome sequencing datasets across various cancer types. We comprehensively profiled structural variations effects on the domain boundaries and the regulation of genes in human cancers. Our findings demonstrate that the impact of TAD disruptions are substantially varied across tumor types and these events are reflective of overall SV burden and type. Notably, most of the TAD disruptions could result in appreciable changes in nearby gene expression in cancer cells. In addition, we demonstrated that SVs can lead to fusion of discrete TADs. Notably, complex rearrangements drastically change chromatin folding maps in the cancer genomes. Note: This abstract was not presented at the meeting. Citation Format: Kadir C. Akdemir. Chromatin folding disruptions in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5227.
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