A-G.21: Interpreting Structural Variations in Breast Cancer Cell Lines Using 3D Genome Data
Keywords
Structural variations, 3D genome, Long-read sequencing
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Structural variations (SVs) are a major source of genomic alterations in cancer, yet the majority of SVs occur in non-coding regions and remain difficult to interpret using linear genome annotations alone. 3D genome data provides additional spatial information for understanding potential regulatory impacts of SVs, but its practical contributions and limitations remain unclear. Here, we perform an integrative analysis of SVs and 3D genome organization in three breast cancer cell lines. Although the majority of SVs occur in non-coding regions, approximately 70% of them are associated with distal gene promoters via high-frequency 3D contacts, revealing potential regulatory relationships beyond linear genome annotations. In the HCC1937 tumor–normal pair under a controlled genetic setting, we observed widespread 3D genome reorganization, including A/B compartment switching affecting roughly one-third of the genome and pronounced insulation score changes at about 30% of somatic SV loci. Detailed analyses of representative somatic SVs further revealed local alterations in topologically associating domain (TAD) structure at SV loci, including the formation of new boundaries or the disruption of pre-existing ones. These SV loci also form high-frequency contacts with distal cancer-related gene loci, such as SLC2A1, HGF, and STAG2, with similar interactions observed for some of these genes in SK-BR-3, suggesting that these spatial associations are common across breast cancer cell lines. These observations indicate that SVs that appear functionally silent under conventional annotation may influence gene regulation through their 3D genome, providing a potential mechanism for prioritizing non-coding variants for further functional investigation.
Co-authors: Yongyi Luo, Jiandong Shi, Depeng Wang, Shu Wang, Xiaodan Fan, Weichuan Yu
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