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Structural variants drive context-dependent oncogene activation in cancer

Author

Listed:
  • 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
    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)

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.

Suggested Citation

  • 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 &, 2022. "Structural variants drive context-dependent oncogene activation in cancer," Nature, Nature, vol. 612(7940), pages 564-572, December.
  • Handle: RePEc:nat:nature:v:612:y:2022:i:7940:d:10.1038_s41586-022-05504-4
    DOI: 10.1038/s41586-022-05504-4
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    Cited by:

    1. Katelyn L. Mortenson & Courtney Dawes & Emily R. Wilson & Nathan E. Patchen & Hailey E. Johnson & Jason Gertz & Swneke D. Bailey & Yang Liu & Katherine E. Varley & Xiaoyang Zhang, 2024. "3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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