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Widespread perturbation of ETS factor binding sites in cancer

Author

Listed:
  • Sebastian Carrasco Pro

    (Boston University)

  • Heather Hook

    (Boston University)

  • David Bray

    (Boston University)

  • Daniel Berenzy

    (The Jackson Laboratory)

  • Devlin Moyer

    (Boston University)

  • Meimei Yin

    (Boston University)

  • Adam Thomas Labadorf

    (Boston University
    Department of Neurology)

  • Ryan Tewhey

    (The Jackson Laboratory)

  • Trevor Siggers

    (Boston University
    Boston University
    Boston University)

  • Juan Ignacio Fuxman Bass

    (Boston University
    Boston University)

Abstract

Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a transcription factor (TF)-aware burden test based on a model of coherent TF function in promoters. We apply this test to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predict 2555 driver NCVs in the promoters of 813 genes across 20 cancer types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We find that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted.

Suggested Citation

  • Sebastian Carrasco Pro & Heather Hook & David Bray & Daniel Berenzy & Devlin Moyer & Meimei Yin & Adam Thomas Labadorf & Ryan Tewhey & Trevor Siggers & Juan Ignacio Fuxman Bass, 2023. "Widespread perturbation of ETS factor binding sites in cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36535-8
    DOI: 10.1038/s41467-023-36535-8
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