TERT promoter mutations and telomeres during tumorigenesis
Introduction
Telomeres are the repetitive elements at the end of linear chromosomes that cap the chromosome end from nucleolytic degradation and protect against a DNA damage response. They comprise tandem hexamers, which serve as a reservoir non-coding DNA, that can buffer terminal sequence loss. Cells can elongate their telomeres using the enzyme telomerase [1]. Most cell-types, however, downregulate telomerase by transcriptionally silencing telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase [2]. In cells without telomerase, telomeres shorten and eventually signal as sites of DNA damage leading to the arrest of cells in a state called replicative senescence [3,4]. Induction of replicative senescence as a consequence of telomere shortening acts as a strong tumor suppressor mechanism in humans [5]. In order to overcome replicative senescence, cancer cells have to inactivate DNA damage signaling (i.e. p53 or CDKN2A) but also stabilize telomeres. More than 90% of all human cancers overcome this proliferative barrier by expressing or re-activating telomerase [6]. Several large scale chromosomal aberrations leading to aberrant TERT expression have been identified: amplifications of the TERT gene [7], transcriptional activation of the TERT gene through viral integrations [8,9], and rearrangements of the TERT locus [10, 11, 12]. Despite the discovery of these important mechanisms, it remained unresolved until recently how TERT is activated for a majority of cancer cases.
Section snippets
The discovery of TERT promoter mutations: prevalence and tissue specificity
A major breakthrough came in 2013, with two studies in melanoma that identified three high frequency hotspot mutations in the TERT promoter at position −57A/C, −124C/T, −146C/T relative to the ATG of the TERT gene [13••,14••] (Figure 1). Soon after, a survey of 60 different tumor types confirmed the high prevalence of TERT promoter mutations (TPMs) in many other cancers, although they occurred with different frequencies: for example, 51% in glioma and 44% in hepatocellular carcinoma (HCC) [15••
Molecular mechanisms of the mutant TERT promoter and ETS factor binding: an unresolved issue
Several studies have worked on elucidating the molecular mechanism of TPMs. TPMs occur heterozygously and in a mutually exclusive fashion [14••,23•,24]. Each of the hotspot mutations creates a de novo ETS (E26 transformation specific) factor binding site. The ETS transcription factor family members share a conserved DNA binding domain that recognizes unique sequences containing GGA(A/T). While some of the transcription factors are restricted to tissue specific expression, others are
Why do cancer cells with TPMs generally have short telomeres and what are the implications?
Despite elevated TERT expression, TPM cancers have short telomeres compared to matched healthy controls. Sequencing-derived length estimates show that telomeres were shorter in TPM samples than in matched normal samples in glioma [38•], clear cell renal cell carcinoma [21] and melanoma [23•]. In the aforementioned TCGA cancer sequencing data of 31 cancer types, telomere length estimates of TPM tumors were lower than those of matched wildtype control samples for almost all analyzed cancer types [
Conclusions and future directions
To date, TPMs are unique in their high prevalence as non-coding mutations and early occurrence across cancer types. While the redundancy of ETS factor binding and the inherent difficulty of targeting a non-coding mutation remain an unresolved challenge in targeting TPMs therapeutically, telomerase inhibition has long been explored as a therapeutic strategy to interfere with telomere elongation and immortalization in cancer cells (reviewed in Ref. [47]). Most of the clinical evaluation for TERT
Author contribution
FL and DH collaboratively wrote this review.
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to thank the members of the Hockemeyer lab and J. Blair and H. Roth for critical comments on the manuscript. D.H. is a Chan Zuckerburg Biohub Investigator and supported by a Research Scholar Grants form the American Cancer Society (133396-RSG-19-029-01-DMC). D.H. is a Pew-Stewart Scholar for Cancer Research supported by the Pew Charitable Trusts and the Alexander and Margaret Stewart Trust. D.H. is supported by the Siebel Stem Cell Institute and N.I.H. [R01-CA196884].
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2022, Archives of Medical ResearchCitation Excerpt :Most likely, tumor formation in such patients and individuals with shorter than average telomeres result from selection of abnormal stem cells following depletion of normal stem cells and/or failure of tumor suppression via telomere erosion. Several distinct mechanisms explain why tumor suppression by progressive telomere erosion unfortunately often fails (46–49). Telomerase activity is upregulated in over 70% of human cancers by TERT point mutations, rearrangements, DNA amplifications and transcript fusions (50,51).
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2022, Cancer GeneticsCitation Excerpt :At first, TERT and telomerase levels are marginal and do not prohibit telomere shortening. Critically short telomeres start accumulating and cells with TERT promoter mutations can then gradually upregulate TERT to stabilize critically short telomeres [23]. Among studies specific to cirrhotic HCC, the putative mechanisms of TERT activation can be divided into three categories: 1) HBV integration events in the TERT promoter [8,24], 2) point mutations (C228T and C250T) in the promoter region mutually exclusive of HBV integration [9,25], and 3) structural variations of the TERT promoter region [8,14].