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Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer

Author

Listed:
  • Carter J. Barger

    (University of California)

  • Abigail K. Suwala

    (University of California
    Heidelberg University Hospital
    German Consortium for Translational Cancer Research (DKTK))

  • Katarzyna M. Soczek

    (University of California)

  • Albert S. Wang

    (University of California)

  • Min Y. Kim

    (University of California)

  • Chibo Hong

    (University of California)

  • Jennifer A. Doudna

    (University of California
    Gladstone Institutes
    University of California
    Lawrence Berkeley National Laboratory)

  • Susan M. Chang

    (University of California
    UCSF Helen Diller Family Comprehensive Cancer Center)

  • Joanna J. Phillips

    (University of California
    UCSF Helen Diller Family Comprehensive Cancer Center
    University of California)

  • David A. Solomon

    (UCSF Helen Diller Family Comprehensive Cancer Center
    University of California)

  • Joseph F. Costello

    (University of California
    UCSF Helen Diller Family Comprehensive Cancer Center)

Abstract

Mutations in the TERT promoter represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants is unknown. In seven cancer types, we identify duplications of wildtype sequence within the core promoter region of TERT that have strikingly similar features including an ETS motif, the duplication length and insertion site. The duplications recruit a GABP tetramer by virtue of the native ETS motif and its precisely spaced duplicated counterpart, activate the promoter and are clonal in a TERT expressing multifocal glioblastoma. We conclude that recurrent TERT promoter duplications are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.

Suggested Citation

  • Carter J. Barger & Abigail K. Suwala & Katarzyna M. Soczek & Albert S. Wang & Min Y. Kim & Chibo Hong & Jennifer A. Doudna & Susan M. Chang & Joanna J. Phillips & David A. Solomon & Joseph F. Costello, 2022. "Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33099-x
    DOI: 10.1038/s41467-022-33099-x
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    References listed on IDEAS

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    1. João Vinagre & Ana Almeida & Helena Pópulo & Rui Batista & Joana Lyra & Vasco Pinto & Ricardo Coelho & Ricardo Celestino & Hugo Prazeres & Luis Lima & Miguel Melo & Adriana Gaspar da Rocha & Ana Preto, 2013. "Frequency of TERT promoter mutations in human cancers," Nature Communications, Nature, vol. 4(1), pages 1-6, October.
    2. Gabrijela Dumbović & Ulrich Braunschweig & Heera K. Langner & Michael Smallegan & Josep Biayna & Evan P. Hass & Katarzyna Jastrzebska & Benjamin Blencowe & Thomas R. Cech & Marvin H. Caruthers & John , 2021. "Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA is driven by intron retention," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    3. Gabrijela Dumbović & Ulrich Braunschweig & Heera K. Langner & Michael Smallegan & Josep Biayna & Evan P. Hass & Katarzyna Jastrzebska & Benjamin Blencowe & Thomas R. Cech & Marvin H. Caruthers & John , 2021. "Publisher Correction: Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA is driven by intron retention," Nature Communications, Nature, vol. 12(1), pages 1-1, December.
    4. Floris P. Barthel & Kevin C. Johnson & Frederick S. Varn & Anzhela D. Moskalik & Georgette Tanner & Emre Kocakavuk & Kevin J. Anderson & Olajide Abiola & Kenneth Aldape & Kristin D. Alfaro & Donat Alp, 2019. "Longitudinal molecular trajectories of diffuse glioma in adults," Nature, Nature, vol. 576(7785), pages 112-120, December.
    5. 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.
    6. Rengyun Liu & Tao Zhang & Guangwu Zhu & Mingzhao Xing, 2018. "Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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