IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33099-x.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33099-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-33099-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Akihiko Fukagawa & Natsuko Hama & Yasushi Totoki & Hiromi Nakamura & Yasuhito Arai & Mihoko Saito-Adachi & Akiko Maeshima & Yoshiyuki Matsui & Shinichi Yachida & Tetsuo Ushiku & Tatsuhiro Shibata, 2023. "Genomic and epigenomic integrative subtypes of renal cell carcinoma in a Japanese cohort," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Miho M. Suzuki & Kenta Iijima & Koichi Ogami & Keiko Shinjo & Yoshiteru Murofushi & Jingqi Xie & Xuebing Wang & Yotaro Kitano & Akira Mamiya & Yuji Kibe & Tatsunori Nishimura & Fumiharu Ohka & Ryuta S, 2023. "TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Josefine Radke & Naveed Ishaque & Randi Koll & Zuguang Gu & Elisa Schumann & Lina Sieverling & Sebastian Uhrig & Daniel Hübschmann & Umut H. Toprak & Cristina López & Xavier Pastor Hostench & Simone B, 2022. "The genomic and transcriptional landscape of primary central nervous system lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Wei-Siang Liau & Qiongyi Zhao & Adekunle Bademosi & Rachel S. Gormal & Hao Gong & Paul R. Marshall & Ambika Periyakaruppiah & Sachithrani U. Madugalle & Esmi L. Zajaczkowski & Laura J. Leighton & Haob, 2023. "Fear extinction is regulated by the activity of long noncoding RNAs at the synapse," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Xing Cheng & Jing An & Jitong Lou & Qisheng Gu & Weimin Ding & Gaith Nabil Droby & Yilin Wang & Chenghao Wang & Yanzhe Gao & Jay Ramanlal Anand & Abigail Shelton & Andrew Benson Satterlee & Breanna Ma, 2024. "Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    6. Oriol Pich & Iker Reyes-Salazar & Abel Gonzalez-Perez & Nuria Lopez-Bigas, 2022. "Discovering the drivers of clonal hematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Diletta Fontana & Ilaria Crespiatico & Valentina Crippa & Federica Malighetti & Matteo Villa & Fabrizio Angaroni & Luca De Sano & Andrea Aroldi & Marco Antoniotti & Giulio Caravagna & Rocco Piazza & A, 2023. "Evolutionary signatures of human cancers revealed via genomic analysis of over 35,000 patients," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    8. Alexander Martinez-Fundichely & Austin Dixon & Ekta Khurana, 2022. "Modeling tissue-specific breakpoint proximity of structural variations from whole-genomes to identify cancer drivers," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Yanli Liu & Zhong Wu & Jin Zhou & Dinesh K. A. Ramadurai & Katelyn L. Mortenson & Estrella Aguilera-Jimenez & Yifei Yan & Xiaojun Yang & Alison M. Taylor & Katherine E. Varley & Jason Gertz & Peter S., 2021. "A predominant enhancer co-amplified with the SOX2 oncogene is necessary and sufficient for its expression in squamous cancer," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    10. Roberta Esposito & Andrés Lanzós & Tina Uroda & Sunandini Ramnarayanan & Isabel Büchi & Taisia Polidori & Hugo Guillen-Ramirez & Ante Mihaljevic & Bernard Mefi Merlin & Lia Mela & Eugenio Zoni & Lusin, 2023. "Tumour mutations in long noncoding RNAs enhance cell fitness," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    11. Osama Al-Dalahmah & Michael G. Argenziano & Adithya Kannan & Aayushi Mahajan & Julia Furnari & Fahad Paryani & Deborah Boyett & Akshay Save & Nelson Humala & Fatima Khan & Juncheng Li & Hong Lu & Yu S, 2023. "Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    12. Zhuoran Xu & Quan Li & Luigi Marchionni & Kai Wang, 2023. "PhenoSV: interpretable phenotype-aware model for the prioritization of genes affected by structural variants," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    13. Kathiresan Selvam & Smitha Sivapragasam & Gregory M. K. Poon & John J. Wyrick, 2023. "Detecting recurrent passenger mutations in melanoma by targeted UV damage sequencing," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    14. Ming Tang & Hussein A. Abbas & Marcelo V. Negrao & Maheshwari Ramineni & Xin Hu & Shawna Marie Hubert & Junya Fujimoto & Alexandre Reuben & Susan Varghese & Jianhua Zhang & Jun Li & Chi-Wan Chow & Xiz, 2021. "The histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    15. Fengju Chen & Yiqun Zhang & Darshan S. Chandrashekar & Sooryanarayana Varambally & Chad J. Creighton, 2023. "Global impact of somatic structural variation on the cancer proteome," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    16. Leland S. Hu & Fulvio D’Angelo & Taylor M. Weiskittel & Francesca P. Caruso & Shannon P. Fortin Ensign & Mylan R. Blomquist & Matthew J. Flick & Lujia Wang & Christopher P. Sereduk & Kevin Meng-Lin & , 2023. "Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    17. Martin Boström & Erik Larsson, 2022. "Somatic mutation distribution across tumour cohorts provides a signal for positive selection in cancer," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    18. 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.
    19. Xiaohan Shi & Yunguang Li & Qiuyue Yuan & Shijie Tang & Shiwei Guo & Yehan Zhang & Juan He & Xiaoyu Zhang & Ming Han & Zhuang Liu & Yiqin Zhu & Suizhi Gao & Huan Wang & Xiongfei Xu & Kailian Zheng & W, 2022. "Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33099-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.