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

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

doi:10.1038/s41467-022-33099-x

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

Nat Commun. 2022 Sep 16;13(1):5430. doi: 10.1038/s41467-022-33099-x.

Authors

Carter J Barger^#¹, Abigail K Suwala^#^{1

2

3}, Katarzyna M Soczek⁴, Albert S Wang¹, Min Y Kim¹, Chibo Hong¹, Jennifer A Doudna^{4

5

6

7

8

9}, Susan M Chang^{1

10}, Joanna J Phillips^{1

10

11}, David A Solomon^{10

11}, Joseph F Costello^{12

13}

Affiliations

¹ Department of Neurological Surgery, University of California, San Francisco, CA, USA.
² Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
³ Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
⁴ Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
⁵ Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA, USA.
⁶ Department of Chemistry, University of California, Berkeley, CA, USA.
⁷ Molecular Biophysics & Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
⁸ Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
⁹ Innovative Genomics Institute, University of California, Berkeley, CA, USA.
¹⁰ UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
¹¹ Department of Pathology, University of California, San Francisco, CA, USA.
¹² Department of Neurological Surgery, University of California, San Francisco, CA, USA. joseph.costello@ucsf.edu.
¹³ UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA. joseph.costello@ucsf.edu.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Glioblastoma* / genetics
Humans
Mutation
Promoter Regions, Genetic* / genetics
Telomerase* / genetics
Telomerase* / metabolism

Substances

TERT protein, human
Telomerase

Abstract

Publication types

MeSH terms

Substances

Grants and funding