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Study Offers Insights Into Role of Structural Variants in Cancer

Combining genomic profiling and genome engineering, a team led by the Salk Institute for Biological Studies' Jesse Dixon has uncovered new details about how some structural variants (SVs) can activate oncogenes to promote cancer. SVs that alter three-dimensional genome organization can lead to enhancer-promoter rewiring and human disease, particularly cancer. But only a small number of SVs are associated with altered gene expression and it is not known why only certain SVs lead to changes in distal gene expression. To investigate, the scientists analyzed Hi-C sequencing data from 92 cancer cell lines and patient samples, finding loci affected by recurrent alterations to 3D genome structure including important oncogenes. As reported in Nature this week, they then used CRISPR/Cas9 genome editing to generate de novo SVs in cell lines and show that oncogene activity can be predicted by using models that consider partner region chromatin contacts and enhancer activity. "Critically, the expression of only a subset of genes is sensitive to these engineered rearrangements, and we observe that only a minority of genes in the genome show evidence of responsiveness to changes in their local enhancer landscape," the study's authors write. "These results indicate that alterations to gene regulatory 3D architecture are a critical mechanism that enables oncogene activation in cancer genomes and sheds light on the essential elements for such gene activation events.