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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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    as
    1. Ludmil B. Alexandrov & Serena Nik-Zainal & David C. Wedge & Samuel A. J. R. Aparicio & Sam Behjati & Andrew V. Biankin & Graham R. Bignell & Niccolò Bolli & Ake Borg & Anne-Lise Børresen-Dale & Sandri, 2013. "Correction: Corrigendum: Signatures of mutational processes in human cancer," Nature, Nature, vol. 502(7470), pages 258-258, October.
    2. Radhakrishnan Sabarinathan & Loris Mularoni & Jordi Deu-Pons & Abel Gonzalez-Perez & Núria López-Bigas, 2016. "Nucleotide excision repair is impaired by binding of transcription factors to DNA," Nature, Nature, vol. 532(7598), pages 264-267, April.
    3. Michael Lawrence & Wolfgang Huber & Hervé Pagès & Patrick Aboyoun & Marc Carlson & Robert Gentleman & Martin T Morgan & Vincent J Carey, 2013. "Software for Computing and Annotating Genomic Ranges," PLOS Computational Biology, Public Library of Science, vol. 9(8), pages 1-10, August.
    4. Ludmil B. Alexandrov & Serena Nik-Zainal & David C. Wedge & Samuel A. J. R. Aparicio & Sam Behjati & Andrew V. Biankin & Graham R. Bignell & Niccolò Bolli & Ake Borg & Anne-Lise Børresen-Dale & Sandri, 2013. "Signatures of mutational processes in human cancer," Nature, Nature, vol. 500(7463), pages 415-421, August.
    5. Michael S. Lawrence & Petar Stojanov & Craig H. Mermel & James T. Robinson & Levi A. Garraway & Todd R. Golub & Matthew Meyerson & Stacey B. Gabriel & Eric S. Lander & Gad Getz, 2014. "Discovery and saturation analysis of cancer genes across 21 tumour types," Nature, Nature, vol. 505(7484), pages 495-501, January.
    6. Esther Rheinbay & Prasanna Parasuraman & Jonna Grimsby & Grace Tiao & Jesse M. Engreitz & Jaegil Kim & Michael S. Lawrence & Amaro Taylor-Weiner & Sergio Rodriguez-Cuevas & Mara Rosenberg & Julian Hes, 2017. "Recurrent and functional regulatory mutations in breast cancer," Nature, Nature, vol. 547(7661), pages 55-60, July.
    7. Fiona M. Behan & Francesco Iorio & Gabriele Picco & Emanuel Gonçalves & Charlotte M. Beaver & Giorgia Migliardi & Rita Santos & Yanhua Rao & Francesco Sassi & Marika Pinnelli & Rizwan Ansari & Sarah H, 2019. "Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens," Nature, Nature, vol. 568(7753), pages 511-516, April.
    8. Serena Nik-Zainal & Helen Davies & Johan Staaf & Manasa Ramakrishna & Dominik Glodzik & Xueqing Zou & Inigo Martincorena & Ludmil B. Alexandrov & Sancha Martin & David C. Wedge & Peter Van Loo & Young, 2016. "Landscape of somatic mutations in 560 breast cancer whole-genome sequences," Nature, Nature, vol. 534(7605), pages 47-54, June.
    9. Yingyao Zhou & Bin Zhou & Lars Pache & Max Chang & Alireza Hadj Khodabakhshi & Olga Tanaseichuk & Christopher Benner & Sumit K. Chanda, 2019. "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    10. Esther Rheinbay & Morten Muhlig Nielsen & Federico Abascal & Jeremiah A. Wala & Ofer Shapira & Grace Tiao & Henrik Hornshøj & Julian M. Hess & Randi Istrup Juul & Ziao Lin & Lars Feuerbach & Radhakris, 2020. "Analyses of non-coding somatic drivers in 2,658 cancer whole genomes," Nature, Nature, vol. 578(7793), pages 102-111, February.
    11. Ludmil B. Alexandrov & Jaegil Kim & Nicholas J. Haradhvala & Mi Ni Huang & Alvin Wei Tian Ng & Yang Wu & Arnoud Boot & Kyle R. Covington & Dmitry A. Gordenin & Erik N. Bergstrom & S. M. Ashiqul Islam , 2020. "The repertoire of mutational signatures in human cancer," Nature, Nature, vol. 578(7793), pages 94-101, February.
    12. Shimin Shuai & Steven Gallinger & Lincoln D. Stein, 2020. "Combined burden and functional impact tests for cancer driver discovery using DriverPower," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    13. Elodie Bal & Rahul Kumar & Mohammad Hadigol & Antony B. Holmes & Laura K. Hilton & Jui Wan Loh & Kostiantyn Dreval & Jasper C. H. Wong & Sofija Vlasevska & Clarissa Corinaldesi & Rajesh Kumar Soni & K, 2022. "Super-enhancer hypermutation alters oncogene expression in B cell lymphoma," Nature, Nature, vol. 607(7920), pages 808-815, July.
    14. Peng Mao & Alexander J. Brown & Shingo Esaki & Svetlana Lockwood & Gregory M. K. Poon & Michael J. Smerdon & Steven A. Roberts & John J. Wyrick, 2018. "ETS transcription factors induce a unique UV damage signature that drives recurrent mutagenesis in melanoma," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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