Abstract 5046: Three-dimensional genome landscape of primary human cancers

Abstract Genome conformation underlies transcriptional regulation by distal enhancers, and genomic rearrangements in cancer can alter critical regulatory interactions. Here we profiled the 3D genome architecture and enhancer connectome of 69 tumor samples spanning 15 primary human cancer types from The Cancer Genome Atlas (TCGA). We discovered three archetypes of enhancer usage for over one hundred oncogenes across human cancers: static, selective gain, or dynamic rewiring. Integrative analyses revealed the enhancer landscape of non-cancer cells in the tumor microenvironment at genes related to immune escape. Deep whole genome sequencing and enhancer connectome mapping provided accurate detection and validation of diverse structural variants across cancer genomes, and revealed distinct enhancer rewiring consequences from noncoding point mutations, genomic inversions, translocations, and focal amplifications. Extrachromosomal DNA promoted more extensive enhancer rewiring of oncogenes among several types of focal amplification mechanisms. These results suggest a systematic approach to understand genome topology in cancer etiology and therapy. Citation Format: Yanding Zhao, Katie E. Yost, King L. Hung, Kaiyuan Zhu, Duo Xu, Ryan Corces, Shadi Shams, Bryan H. Louie, Shahab Sarmashghi, Laksshman Sundaram, Jens Luebeck, Stanley Clarke, Ashley S. Doane, Jeffrey M. Granja, Hani Choudhry, Marcin Imieliński, Andrew D. Cherniack, Ekta Khurana, Vineet Bafna, Ina Felau, Jean C. Zenklusen, Peter W. Laird, Christina Curtis, Cancer Genome Atlas Analysis Network, William J. Greenleaf, 1 Howard Y. Chang. Three-dimensional genome landscape of primary human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5046.