Structural variants drive context-dependent oncogene activation in cancer

Zhichao Xu, Dong-Sung Lee, Sahaana Chandran, Victoria T. Le, Rosalind Bump, Jean Yasis, Sofia Dallarda, Samantha Marcotte, Benjamin Clock, Nicholas Haghani, Chae Yun Cho, Kadir C. Akdemir, Selene Tyndale, P. Andrew Futreal, Graham McVicker, Geoffrey M. Wahl and Jesse R. Dixon ()
Additional contact information
Zhichao Xu: Gene Expression Laboratory; Salk Institute for Biological Studies
Dong-Sung Lee: University of Seoul
Sahaana Chandran: Gene Expression Laboratory; Salk Institute for Biological Studies
Victoria T. Le: Gene Expression Laboratory; Salk Institute for Biological Studies
Rosalind Bump: Gene Expression Laboratory; Salk Institute for Biological Studies
Jean Yasis: Gene Expression Laboratory; Salk Institute for Biological Studies
Sofia Dallarda: Gene Expression Laboratory; Salk Institute for Biological Studies
Samantha Marcotte: Gene Expression Laboratory; Salk Institute for Biological Studies
Benjamin Clock: Gene Expression Laboratory; Salk Institute for Biological Studies
Nicholas Haghani: Gene Expression Laboratory; Salk Institute for Biological Studies
Chae Yun Cho: Gene Expression Laboratory; Salk Institute for Biological Studies
Kadir C. Akdemir: UT MD Anderson Cancer Center
Selene Tyndale: Integrative Biology Laboratory; Salk Institute for Biological Studies
P. Andrew Futreal: UT MD Anderson Cancer Center
Graham McVicker: Integrative Biology Laboratory; Salk Institute for Biological Studies
Geoffrey M. Wahl: Gene Expression Laboratory; Salk Institute for Biological Studies
Jesse R. Dixon: Gene Expression Laboratory; Salk Institute for Biological Studies

Nature, 2022, vol. 612, issue 7940, 564-572

Abstract: Abstract Higher-order chromatin structure is important for the regulation of genes by distal regulatory sequences1,2. Structural variants (SVs) that alter three-dimensional (3D) genome organization can lead to enhancer–promoter rewiring and human disease, particularly in the context of cancer3. However, only a small minority of SVs are associated with altered gene expression4,5, and it remains unclear why certain SVs lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific rearrangements on oncogene activation. By analysing Hi-C data from 92 cancer cell lines and patient samples, we identified loci affected by recurrent alterations to 3D genome structure, including oncogenes such as MYC, TERT and CCND1. By using CRISPR–Cas9 genome engineering to generate de novo SVs, we show that oncogene activity can be predicted by using ‘activity-by-contact’ models that consider partner region chromatin contacts and enhancer activity. However, activity-by-contact models are only predictive of specific subsets of genes in the genome, suggesting that different classes of genes engage in distinct modes of regulation by distal regulatory elements. These results indicate that SVs that alter 3D genome organization are widespread in cancer genomes and begin to illustrate predictive rules for the consequences of SVs on oncogene activation.

Date: 2022
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DOI: 10.1038/s41586-022-05504-4

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