Next Article in Journal
A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage
Previous Article in Journal
The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 9
Issue 3
10.3390/cells9030749
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Solo Play of TERT Promoter Mutations

by
François Hafezi
and
Danielle Perez Bercoff
*
Department of Infection and Immunity, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg
*
Author to whom correspondence should be addressed.
Cells 2020, 9(3), 749; https://doi.org/10.3390/cells9030749
Submission received: 11 February 2020 / Revised: 16 March 2020 / Accepted: 16 March 2020 / Published: 19 March 2020
(This article belongs to the Section Cell Signaling)
Browse Figures
Versions Notes

Abstract

:
The reactivation of telomerase reverse transcriptase (TERT) protein is the principal mechanism of telomere maintenance in cancer cells. Mutations in the TERT promoter (TERTp) are a common mechanism of TERT reactivation in many solid cancers, particularly those originating from slow-replicating tissues. They are associated with increased TERT levels, telomere stabilization, and cell immortalization and proliferation. Much effort has been invested in recent years in characterizing their prevalence in different cancers and their potential as biomarkers for tumor stratification, as well as assessing their molecular mechanism of action, but much remains to be understood. Notably, they appear late in cell transformation and are mutually exclusive with each other as well as with other telomere maintenance mechanisms, indicative of overlapping selective advantages and of a strict regulation of TERT expression levels. In this review, we summarized the latest literature on the role and prevalence of TERTp mutations across different cancer types, highlighting their biased distribution. We then discussed the need to maintain TERT levels at sufficient levels to immortalize cells and promote proliferation while remaining within cell sustainability levels. A better understanding of TERT regulation is crucial when considering its use as a possible target in antitumor strategies.

1. Introduction

Telomeres and their associated shelterin complex are located at chromosomal ends. Telomeres are tandem repeats of TTAGGG up to 15 kb long in humans. Together, telomeres and the shelterin complex protect chromosomal ends and preserve genomic DNA integrity [1,2,3,4]. Telomeres are shortened with each cell division. When telomere length falls below a critical threshold, cells become replicatively senescent and undergo apoptosis [5]. Cancer cells circumvent replicative telomere shortening by stabilizing them [6] through one of two mechanisms: reactivation of telomerase, the enzyme that extends telomeres (85–90% of cancers) [7,8,9,10], or homologous recombination between sister chromatids, a phenomenon termed alternative lengthening of telomeres (ALT) (3–10% of cancers) [10,11,12]. Telomerase is a ribonuclear holoenzyme composed of an RNA template (TERC) and a reverse transcriptase catalytic subunit (TERT) [1,2,3,4,13]. TERT is silent in most somatic cells, and is reactivated in cancer cells, endowing them with unrestricted proliferation capacity [6,14,15,16].
Although TERT activity is regulated principally at the transcriptional level (reviewed in References [3,4,9,17,18,19,20,21,22]), it may also be regulated through splicing [23,24], post-translational modifications, or intracellular trafficking [25,26,27,28]. The TERT promoter (TERTp) contains binding sites for numerous transcriptional activators including Sp-1, c-Myc, Hypoxia Induced Factor (HIF), AP-2, β-catenin, NF-κB, E-twenty-six (Ets)/ternary complex factors (TCF) family members, and transcriptional repressors (Wilms’ tumor (WT1), TP53, Nuclear Transcription Factor, X-Box Binding (NFX-1), Mad-1 and CCCTC binding factor (CTCF)) [3,4,9,17,18,19,20,21,29]. TERT expression can be reactivated by copy number variants (CNV), TERT or TERTp structural variants, chromosomal rearrangements juxtaposing TERTp to enhancer elements, cellular and viral oncogenes such as Hepatitis B virus (HBV) X protein (HBx) or high-risk Human papillomavirus (HPV)16 and HPV18 E6 oncoprotein, and, last but not least, mutations within TERTp (31% of TERT-expressing cancers) (Figure 1A) [10,30,31,32,33,34,35,36,37,38] (reviewed in [3,4,9,18,19,20,39]). Increased TERTp methylation is typically recorded in >50% of TERT-expressing tumors and cell lines [10,40,41,42,43,44,45,46,47]. Epigenetic regulation of TERTp is based on altered methylation patterns of specific regions. Hypomethylation of the region between −200 and −100 from the Translational Start site (TSS), encompassing the core promoter, enables binding of c-Myc and Sp-1, thus reactivating transcription. In contrast, the region spanning exon 1 (positions +1 to ±100 from the TSS) contains a binding site for the DNA insulator CTCF. Hypermethylation of this region disrupts binding of CTCF and therefore allows TERT transcription [41,42,43,44]. Similarly, the region between −600 and −200 from the TSS contains a second CTCF binding site and is partially hypermethylated in TERT-expressing cells [41,42,43,44]. The transcriptional control of TERT has been comprehensively reviewed recently [3,4,9,18,19,20,21,22,29,48] and, as such, is beyond the scope of this review. In this review, we focused on the distribution and exclusiveness of TERTp mutations.

2. Telomerase Reverse Transcriptase Promoter (TERTp) Mutations

TERTp mutations were first described in congenital and sporadic melanoma in 2013 [49,50]. Subsequent large-scale cohort studies together with seminal mechanistic studies both ascertained the TERTp mutation prevalence in many other forms of cancer and characterized their mode of action.
The two main TERTp mutations are located at positions 1,295,228 and 1,295,250 on Chromosome 5, and generate C to T transitions. They are located 124 and 146 base pairs upstream from the TERTp TSS (Figure 1B). Less frequent tandem mutations −125/−124 CC>TT and −139/−138 CC>TT have been reported in cutaneous tumors (Table 1) [49,51]. While these are somatic mutations, a germline mutation at position −57A>C from the TSS has been identified in familial melanomas and showed similar effects [49]. All of these mutations have similar effects, increasing TERT expression ~2–6 fold as measured through qRT-PCR, immunohistochemistry, TRAP, or reporter vectors in numerous cancer types, as outlined in Table 1 [37,50,52,53,54,55,56,57,58,59,60,61,62,63,64,65]. This increased TERT expression maintains self-renewal potential and telomeres in both stem cells and terminally differentiated bladder cells, indicating that these mutations are sufficient to immortalize cells [66,67].
All of these TERTp mutations (at positions −146, −124, −57, and −139/−138) create novel Ets/TCF transcription factor binding sites. The Ets/TCF transcription factors bind to GGAA motifs (or TTCC on the opposite strand). The 30 members of the Ets/TCF-family transcription factors are important contributors to oncogenesis and include Ets-1, Ets-2, and GA binding protein (GABP) [68]. So far, GABP has been reported to selectively bind the −124 C>T and −146 C>T mutations in GBM, melanoma, and urothelial bladder cancer cell lines [69,70,71]. Unlike the other Ets/TCF family transcription factors, GABP is an obligate dimer of GABPA and GABPB dimers. It binds two nearby in-phase GGAA sites [68,72,73,74] positioned 1, 2, or n helical turns away from each other [69], or brought close together by DNA looping [70]. TERTp mutations are associated with epigenetically active chromatin [54,69,75,76]. Intriguingly, whereas methylation of wild-type (wt) TERT promoter is associated with TERT expression [10,43,44], TERTp mutations are associated with decreased TERTp methylation [76]. The −146 C>T mutation was also shown to bind the non-canonical NF-κB-p52 and Ets-1/2 [59].
TERTp mutations have been recorded in a wide range of solid cancers. They are present in primary gliomas and glioblastoma multiforme (GBM), oligodendrogliomas and astrocytomas [10,40,52,53,54,57,58,60,64,65,77,78,79,80,81,82,83,84,85,86], melanomas, cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) [49,50,51,52,55,87,88,89,90,91], myxoid liposarcomas [77], urothelial bladder carcinoma [50,57,78,92,93,94], hepatocellular carcinoma (HCC) [50,57,62,95,96,97], and thyroid cancers [98,99,100,101,102,103,104,105,106], as well as oral and cervical SCC [36,37,57] (Table 1). Furthermore, they were consistently found in tumor cell lines derived from these malignancies [37,50,52,54,58,62,97,100,107,108]. TERTp mutations often arise in tissues with low rates of self-renewal (brain, thyroid) [77], where they provide an immediate competitive advantage to cells that acquire them. Conversely, they appear to be infrequent (<15%) in hematopoietic, lymphoid, or gastrointestinal malignancies. These are from compartments with high cellular turnover and intrinsic telomerase activity. Here, the endogenously elevated TERT levels likely render TERTp mutations neutral [3,38,57,77,109].

3. Cancer Distribution of TERTp Mutations

The clinicopathological association of TERTp mutations is cancer-dependent. It is a consideration for fine tumor stratification and orientation of patients towards personalized treatments, and provides insight into the process of cellular transformation.

3.1. Gliomas and Glioblastoma (GBM)

GBM are WHO Grade IV tumors of the central nervous system (CNS). Primary GBM evolve rapidly without prior low-grade lesions, while secondary GBM progress slowly from diffuse or anaplastic astrocytoma and oligodendroglioma (WHO Grade II and III). Primary and secondary GBM differ genetically more than histologically. The 2016 WHO classification of CNS tumors is based on “integrated diagnosis” including histology and isocitrate dehydrogenase (IDH)-1/2 mutations (a biomarker for secondary GBM), and the presence of the 1p/19q codeletion (a marker for oligodendroglioma) [110]. TERTp mutations are relatively rare in diffuse (17.7%, range 10–19%) and anaplastic astrocytomas (24.7%, range 10–62.5%), as well as in IDH-mutated gliomas and secondary GBM (~28%). Their prevalence is highest (64.7%, range 45–88.6%) in oligodendrogliomas (where they coexist with the 1p/19q full deletion [53]) and in primary GBM (68%, range 44–100%) (Table 1) [38,52,53,65,77,80,81,84,85,111]. They tend to be found mainly in samples with epidermal growth factor receptor (EGFR) amplification, an early feature of primary GBM, [64,77,111]. Conversely, they appear to be mutually exclusive with mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and Death Domain Associated Protein (DAXX) [38,65,77,79,80,110,111,112], two telomere-binding proteins mutated in ALT [11,12].
TERTp mutations are independently associated with older age, late clinical stage, poor prognosis, and shorter overall survival (OS) in GBM/glioma and IDH-wt astrocytoma patients. The presence of TERTp mutations alone is associated with a worse prognosis than TERTp mutations together with IDH-mutations [4,60,64,65,77,79,80,81,84,85,112]. Conversely, GBM patients with ALT and no TERTp mutations have longer OS than patients with TERTp mutations only [77,112,113]. In terms of treatment, Grade II and III IDH-wt CNS tumors generally respond to adjuvant radiation and chemotherapy with temozolomide (TMZ). However, the presence of TERTp mutations decreases sensitivity to genotoxic therapies. It has therefore been proposed to use TERTp mutations to further stratify IDH-wt Grade II and III gliomas into subgroups to orient treatment [60,81,114].

3.2. Melanoma and Non-Melanoma Skin Carcinoma

In patients with primary melanoma, TERTp mutations have been reported in 39.2% (range 22–71%) of tumors. They arise progressively in sun-exposed sites and have been attributed to UV radiation. They are associated with increased patient age, distal metastases, poor outcome, and compromised OS and disease-free survival (DFS) [49,50,51,52,88,89,115]. In ~50% of cases, they are associated with mutations in BRAF/NRAS [49,52,88,89,91,116], influencing OS in the following order: TERTpmut+BRAF/NRASmut<TERTpmut~BRAF/NRASmut<TERTp-wt+BRAF/NRAS-wt [56].
Consistent with their UV-induced origin in skin cancers, TERTp mutations are also highly prevalent at sun-exposed sites in non-melanoma squamous cell (50%) and basal cell carcinomas (46.2%, range 38–74%), the most common skin tumor [55,89,90]. TERTp mutations display unique features in melanoma and non-melanoma cancers. First, −146 C>T and −124 C>T occur with similar frequencies in contrast to all other cancers, where −124 C>T is by far the most prevalent mutation (Table 1). Second, −139/−138 CC>TT and −125/−124 CC>TT tandem mutations are often reported. Third, TERTp mutations were detected in 9/10 melanomas with ALT in one study [117] and together (−124 C>T + −146 C>T) in two patients with BCC in another study [89], indicating that more than one telomere maintenance mechanism can, unusually, coexist in skin cancers.

3.3. Urothelial Bladder Cancer

TERTp mutations have been detected in 64.6% (range 29.5–100%) of urothelial bladder and upper urinary tract cancers. They are the most common somatic lesions in this cancer type [52,57,61,77,92,94,118,119]. They have been associated with reduced survival, disease recurrence, and distal metastases [61,118,119], although there appears to be no difference between early- and late-stage patients [52,94].

3.4. Thyroid

Among thyroid cancers, TERTp mutations have been reported mainly in follicular-cell-derived thyroid malignancies (papillary thyroid carcinoma (PTC): 13.4%, range 4.1–37.7%; follicular thyroid carcinoma (FTC): 13.9%, range 5.9–66.7%; poorly differentiated thyroid carcinoma (PDTC): 43.7%, range 21–51.7%; and anaplastic thyroid carcinomas (ATC): 39.7%, range 13–50%). The presence of TERTp mutations is significantly associated with increased age, tumor size and stage, distal metastases, tumor recurrence, and shorter OS and DFS in PTC and FTC. Their prevalence increases from differentiated PTC and FTC to the more aggressive poorly differentiated ATC (Table 1) [98,99,100,101,102,103,104,105,106]. The association of TERTp mutations with the common BRAF-V600E mutation is a powerful predictor of poor OS and DFS [52,98,99,104,105,106,108]. As in glioma, TERTp mutations compromise the outcome of radioiodine therapy [101,105].

3.5. Hepatocellular Carcinoma (HCC)

TERTp mutations are an early event in hepatocellular tumorigenesis [57,62,77,95]. They are not only seen in established HCC (47.1%, range 29.3–65.4%). As hepatocellular adenomas transform into HCC, TERTp mutations are the first gene recurrently mutated after β-catenin (CTNNB1) in preneoplastic cirrhotic lesions [62,95]. Together with the CTNNB1 mutation, TERTp mutations are considered critical effectors of malignant transformation. As such, they have been proposed as early biomarkers for hepatocellular transformation [62,77,95,96,120,121].
TERTp mutations appear to be more frequent in HCV-associated HCC [62,77,95,96,122] and less frequent or excluded from HBV-associated HCC [62,96,121,122], although this remains controversial [63,77,95]. HBV DNA insertion in the TERTp is a recurrent mechanism of TERT transcriptional reactivation in HBV-associated HCC [34,123,124], and a genetic screen of TERT in HCC found TERTp mutations to be mutually exclusive with HBV integration, TERT CNVs, and ATRX mutations [121].

3.6. Cervical and Oral Head and Neck Squamous Cell Carcinoma (HNSCC)

TERTp mutations were detected in cervical SCC (20.1%, range 4.5–21.8%) and HNSCC (22.5%, range 17–31.7%) [36,37]. These malignancies are often associated with high-risk-HPV16/18 E6 and E7 viral oncoproteins and with APOBEC mutations [125,126,127]. High-risk HPV–E6 transactivates TERT [30,32,33,128,129]. TERTp mutations have a notably higher prevalence in HPV-negative cervical and oral SCC. This gives distinct patterns of TERT reactivation through mutually exclusive mechanisms [36,37]. In cervical SCC, they are associated with higher TERT levels than HPV16/18-E6-positive tumors and with advanced cervical cancer [36,37]. Broader studies are needed to evaluate the added value of screening for the molecular mechanism underlying TERT reactivation in cervical and oral SCC.

3.7. The rs2853669 Polymorphism

Among TERT polymorphisms, a common polymorphism (rs2853669 A>G) which disrupts a pre-existing Ets/TCF binding site located 245 bp upstream of the TERT TSS has been reported to modify the effect of TERTp mutations. It decreases TERT transcription in vitro and reverses TERT upregulation by TERTp mutations [56,61,81,85,130]. Controversial clinical impacts have been reported, from a beneficial effect on OS and limited tumor recurrence in TERTp-mutated urothelial bladder cancer, renal clear cell carcinoma, melanoma, and GBM [56,61,81,85,116,131], to unchanged or worsened clinical outcome in GBM, melanoma, or differentiated thyroid carcinomas [64,65,84,91,102,103]. In HCC, the rs2853669 polymorphism in combination with TERTp mutations has been associated with decreased OS and DSF, and increased TERTp methylation and expression [47]. Possible reasons for these conflicting reports could be homozygosity versus heterozygosity of the variant, or its occurrence on the same allele as TERTp mutations. Further studies are needed to assess the relevance of screening for this polymorphism for prognostic and treatment purposes.

4. Cancer Bias of TERTp Mutations

TERTp mutations have been recorded in individuals of Caucasian, African, and Asian descent, with no race-related bias. The −124 C>T mutation has an overwhelmingly higher prevalence than the −146 C>T mutation in all cancers, with the exception of skin cancers, where both hotspots are mutated with comparable frequencies (Figure 2 and Table 1). Although both −124C>T and −146C>T mutations generate identical sequences, enable binding of GABPA, and are equally efficient in increasing TERT transcription in vitro [57,69], in vivo, the −124 C>T mutation was associated with higher TERT mRNA in GBM [57,112]. This would suggest that the Ets/TCF binding site at position −124 provides a more favorable or accessible hotspot for the transcriptional machinery [109]. The overrepresentation of the −146 C>T mutation in skin cancers hints at different etiologies of TERTp mutations. TERTp mutations in melanoma and non-melanoma skin cancers have been attributed to UV damage [49,51,55,88,89,90,91,116], which triggers C→T transitions at CC dinucleotides [55,127]. Nevertheless, C→T transitions where C is preceded by C also conform to the preferred target of Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC)3A/B de-aminations and to aging mutations [127,133]. APOBEC3 mutations are highly prevalent in ovarian and HPV-associated cervical and oral SCC [125,126,127], as well as in HCC and in cirrhotic lesions [121,134]. A role for APOBEC and aging-associated de-aminations is consistent with potentially increased accessibility of the −124 position to DNA binding proteins and with the association of TERTp mutations with older age at diagnosis in GBM, melanoma, and PTC [52,57,60,63,64,77,79,80,82,86,88,98,100,101,102]. These observations therefore raise the possibility that UV-driven lesions account for TERTp mutations in skin cancers, while APOBEC and age-driven de-aminations account for the −124 C>T mutation in other cancers. Further epidemiological and mechanistic studies are needed to shed light on this point.
The −139/−138 CC>TT tandem mutation is very infrequent, limited to skin cancers, and has been associated with lower DFS. This tandem mutation has been suggested to favor chromosomal instability [51].

5. Exclusiveness of TERTp Mutations

Aside from non-melanoma skin cancers [90], TERTp mutations are mostly monoallelic. This suggests that TERT reactivation on one allele is probably sufficient to ensure telomere maintenance or elongation in cancer cells [54]. In line with this observation, TERTp mutations appear to be mutually exclusive [50]. Likewise, TERTp mutations are generally absent from cancers where telomere elongation is ensured by ALT [77,79,80,98] or TERT copy-number duplications [38,121]. TERTp mutations are also less frequent in cancers where viral transformation or viral oncogenes reactivate TERT transcription, such as HBV-DNA or high-risk HPV16/18 E6 [30,32,33,36,37,62,95,96,121,122]. These observations reinforce the concept that, despite some exceptions [38,89,111,117], tumors generally rely on one mechanism for telomere maintenance. The reasons for such selectivity remain speculative to date. One possible explanation is that there is a threshold for TERT expression, above which the biological advantage is lost.
Consistent with this view, Phosphatidyl Inositol Kinase 3 (PIK3) CA and PIK3 Receptor 1 (PIK3R1) mutations are recorded in 50% of GBM with wt TERTp and tend to be mutually exclusive with TERTp mutations in ovarian clear cell carcinoma [79,86,132]. The PIK3CA/Akt signaling pathway is involved in cellular self-renewal in embryonic stem cells and cancer stem cells [135], as well as in TERT Ser227 and Ser824 phosphorylation, subsequent nuclear translocation, and cellular transformation [25,26,27,28]. Mutual exclusion of PIK3CA and TERTp mutations suggests that activation of the PIK3CA/Akt pathway or of TERT confer cells a similar growth and proliferative advantage. In the absence of TERT reactivation, other telomere maintenance mechanisms, such as ALT, can achieve immortalization [27]. Indeed, TERT also contributes to cell survival and proliferation through telomere-independent mechanisms; it facilitates Wnt/β-catenin-dependent [136,137], c-myc-dependent [138,139], and NF-κB-dependent gene transcription [140,141], thereby sustaining both oncogenic signaling pathways and its own transcription in a feedforward loop [29,142]. It also regulates methylation [48,143] and DNA damage responses [144,145], and protects cells from Endoplasmic Reticulum (ER) stress and apoptosis by buffering Reactive Oxygen Species (ROS) and modulating mitochondrial function [145,146,147,148,149,150,151]. It is highly likely that TERT homeostasis is also tuned by these functions within a given tumor type and microenvironment, and by related metabolic alterations that need to be preserved.

6. Discussion

Hints for a model come from the observation that overall, TERTp mutations are associated with late-stage disease in GBM, melanoma, urothelial, and thyroid carcinoma [49,52,60,61,66,85,98,100,101,103,104,105,112,118] and with the last steps of hepatocellular transformation [62,95]. They often occur with or after mutations in pathways associated with cell growth and proliferation. In GBM, TERTp mutations coexist with EGFR amplification [64,77,111], and in urothelial bladder carcinoma, they are associated with FGFR3 (Fibroblast Growth Factor Receptor 3) mutations [61,94]. In ~50% of melanoma, urothelial, and thyroid cancers, TERTp mutations coexist with the common BRAF-V600E mutation [52,88,89,105,106,108,116,152]. GFR and BRAF/RAS kinases control the MAPK and PI3K-Akt pathways that lead to cell growth, survival, and angiogenesis. Constitutive activation of the GFR/FGFR-BRAF/RAS pathway leads to constitutive cell growth and division [153]. Mutations in these oncogenes are often detectable in low-grade tumors and probably precede TERTp mutations [22,61,77,112]. The picture is even more clear-cut in HCC, where mutations in β-catenin (CTNNB1) neatly precede TERTp mutations during the process of malignant transformation [62,95,120]. β-catenin is involved in cell adhesion and interacts with Wnt, promoting cell growth and division. The proliferative advantage conferred by driver mutations in these pathways leads to accelerated telomere erosion. Accordingly, most tumors display telomere dysfunction and shortened telomeres, which leads to chromosome instability [10,22,61,66,98,112,115]. In this scenario, TERT reactivation regenerates telomeres sufficiently to maintain them above the critical threshold and to stabilize the tumor genome [3,18,145]. This interpretation is consistent with the association of TERTp mutations with shortened telomeres and with age as in PTC, melanoma, and GBM/glioma, since cells from younger patients or with sufficiently long telomeres do not need to rely on telomerase reactivation to overcome telomeric crisis [10,29,57,77,85,98,101,115]. Partial telomere healing is coherent with a modest increase in TERT expression (2- to 4-fold) and with a single genetic mechanism of telomere elongation. It likely reflects an exquisite balance between escape from apoptosis resulting from telomere attrition and genomic instability, and cell sustainability in terms of oxygen and nutrient supplies.
Intriguingly, it was recently reported that GABPA controls the cell cycle and induces cell differentiation, thus acting as a tumor suppressor regulating cell proliferation, stemness, and adhesion. It decreased tumor invasiveness and distal metastases in PTC, HCC, and bladder carcinoma [154,155,156]. GABPA levels were decreased and even negatively associated with TERT expression in PTC [154,155,156]. One possible explanation is that other Ets/TCF family transcription factors bind TERTp mutations. Alternatively, the decrease in GABPA expression may follow rather than precede TERTp mutations. In this case, it would be a cellular adaptation which confers a selective advantage to TERTp-mutated (and GFR/BRAF/RAS-mutated) cells by containing TERT reactivation within sustainable limits. Decreased GABPA could also be an adaptation to the TERT-induced proliferation, stemness, and invasion to avoid contradictory signals. Further studies establishing the order of emergence of these mutations would be needed to shed light on this matter.
Taken together, these observations point to a fine tuning of TERT homeostasis and suggest that there is a narrow kinetic and quantitative window for TERT expression. Below that window, cells succumb to telomere crisis and DNA damage. Above that window, cells succumb to overwhelming genetic alterations or metabolic needs. This frailty could be exploited through strategies aiming to push cells either way beyond the threshold of TERT tolerability.

7. Concluding Remarks

TERTp mutations have only been described recently; however, they have prompted an impressive number of studies which draw a comprehensive picture of their prevalence across cancers, as well as providing clues on their mechanisms of action and their associated constraints. They have been proposed as potential biomarkers with predictive and treatment-orienting value. However, more structured studies are needed to validate their clinical potential, particularly since they appear at different stages in different malignancies, ranging from preneoplastic cirrhotic lesions to late stage GBM or melanoma with distal metastases. Cancer cells only require one mechanism of telomere maintenance. This underscores the key role of telomere stabilization in the process of transformation, as well as the necessity of maintaining an exquisitely balanced TERT homeostasis to achieve tumor cell selection, adaptation, and sustainability. TERT is a target of choice in antitumor strategies due to its reactivation in numerous cancers. A better understanding of TERT regulation, homeostasis, and functions could help to overcome the shortcomings of prior genetic and immunotherapy-based approaches targeting TERT.

Author Contributions

F.H. and D.P.B. wrote the manuscript and approved the final version. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Ministère de l’Education et de la Recherche du Luxembourg; FH is supported by the Fonds National de la Recherche du Luxembourg FNR-PRIDE scheme (PRIDE/11012546/NEXTIMMUNE).

Acknowledgments

The authours are deeply grateful to Dr Jonathan D Turner for his thorough revision of this manuscript and for his insightful advise.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ALTAlternative lengthening of telomeres
ATCAnaplastic thyroid carcinoma
ATRXα-Thalassemia/mental retardation syndrome X-linked
BCCBasal cell carcinoma
CNSCentral nervous system
CNVCopy number variant
DAXXDeath-domain-associated protein
DFSDisease-free survival
DTCDifferentiated thyroid carcinoma
EGFREpidermal growth factor receptor
FTCFollicular thyroid carcinoma
GBMGlioblastoma multiforme
HBVHepatitis B virus
HBxHepatitis B X protein
HCCHepatocellular carcinoma
HCVHepatitis C virus
HNSCCHead and neck squamous cell carcinoma
HPVHuman papillomavirus
IDHIsocytrate dehydrogenase
OSOverall survival
PDTCPoorly differentiated thyroid carcinoma
PTCPapillary thyroid carcinoma
ROSReactive oxygen species
SCCSquamous cell carcinoma
TERTTelomerase reverse transcriptase
TERTpTERT promoter
TFTranscription factor
TMZTemozolomide
TSSTranslational start site

References

  1. Greider, C.W. Telomere length regulation. Annu. Rev. Biochem. 1996, 65, 337–365. [Google Scholar] [CrossRef]
  2. Robles-Espinoza, C.D.; Velasco-Herrera Mdel, C.; Hayward, N.K.; Adams, D.J. Telomere-regulating genes and the telomere interactome in familial cancers. Mol. Cancer Res. 2015, 13, 211–222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Heidenreich, B.; Kumar, R. TERT promoter mutations in telomere biology. Mutat. Res. 2017, 771, 15–31. [Google Scholar] [CrossRef]
  4. Leao, R.; Apolonio, J.D.; Lee, D.; Figueiredo, A.; Tabori, U.; Castelo-Branco, P. Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: Clinical impacts in cancer. J. Biomed. Sci. 2018, 25, 22. [Google Scholar] [CrossRef]
  5. Bodnar, A.G.; Ouellette, M.; Frolkis, M.; Holt, S.E.; Chiu, C.P.; Morin, G.B.; Harley, C.B.; Shay, J.W.; Lichtsteiner, S.; Wright, W.E. Extension of life-span by introduction of telomerase into normal human cells. Science 1998, 279, 349–352. [Google Scholar] [CrossRef] [Green Version]
  6. Liu, L.; Lai, S.; Andrews, L.G.; Tollefsbol, T.O. Genetic and epigenetic modulation of telomerase activity in development and disease. Gene 2004, 340, 1–10. [Google Scholar] [CrossRef]
  7. Holt, S.E.; Wright, W.E.; Shay, J.W. Regulation of telomerase activity in immortal cell lines. Mol. Cell Biol. 1996, 16, 2932–2939. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Yasumoto, S.; Kunimura, C.; Kikuchi, K.; Tahara, H.; Ohji, H.; Yamamoto, H.; Ide, T.; Utakoji, T. Telomerase activity in normal human epithelial cells. Oncogene 1996, 13, 433–439. [Google Scholar] [PubMed]
  9. Akincilar, S.C.; Unal, B.; Tergaonkar, V. Reactivation of telomerase in cancer. Cell Mol. Life Sci. 2016, 73, 1659–1670. [Google Scholar] [CrossRef] [Green Version]
  10. Barthel, F.P.; Wei, W.; Tang, M.; Martinez-Ledesma, E.; Hu, X.; Amin, S.B.; Akdemir, K.C.; Seth, S.; Song, X.; Wang, Q.; et al. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat. Genet. 2017, 49, 349–357. [Google Scholar] [CrossRef]
  11. Heaphy, C.M.; Subhawong, A.P.; Hong, S.M.; Goggins, M.G.; Montgomery, E.A.; Gabrielson, E.; Netto, G.J.; Epstein, J.I.; Lotan, T.L.; Westra, W.H.; et al. Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am. J. Pathol. 2011, 179, 1608–1615. [Google Scholar] [CrossRef]
  12. Redon, S.; Reichenbach, P.; Lingner, J. The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. Nucleic Acids Res. 2010, 38, 5797–5806. [Google Scholar] [CrossRef] [Green Version]
  13. Feng, J.; Funk, W.D.; Wang, S.S.; Weinrich, S.L.; Avilion, A.A.; Chiu, C.P.; Adams, R.R.; Chang, E.; Allsopp, R.C.; Yu, J.; et al. The RNA component of human telomerase. Science 1995, 269, 1236–1241. [Google Scholar] [CrossRef]
  14. Wright, W.E.; Piatyszek, M.A.; Rainey, W.E.; Byrd, W.; Shay, J.W. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 1996, 18, 173–179. [Google Scholar] [CrossRef]
  15. Stewart, S.A.; Hahn, W.C.; O’Connor, B.F.; Banner, E.N.; Lundberg, A.S.; Modha, P.; Mizuno, H.; Brooks, M.W.; Fleming, M.; Zimonjic, D.B.; et al. Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc. Natl. Acad. Sci. USA 2002, 99, 12606–12611. [Google Scholar] [CrossRef] [Green Version]
  16. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [Green Version]
  17. Kyo, S.; Takakura, M.; Fujiwara, T.; Inoue, M. Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. Cancer Sci. 2008, 99, 1528–1538. [Google Scholar] [CrossRef] [Green Version]
  18. Liu, T.; Yuan, X.; Xu, D. Cancer-specific telomerase reverse transcriptase (tert) promoter mutations: Biological and clinical implications. Genes 2016, 7, 38. [Google Scholar] [CrossRef]
  19. Bell, R.J.; Rube, H.T.; Xavier-Magalhaes, A.; Costa, B.M.; Mancini, A.; Song, J.S.; Costello, J.F. Understanding tert promoter mutations: A common path to immortality. Mol. Cancer Res. 2016, 14, 315–323. [Google Scholar] [CrossRef] [Green Version]
  20. Ramlee, M.K.; Wang, J.; Toh, W.X.; Li, S. Transcription regulation of the human telomerase reverse transcriptase (hTERT) gene. Genes 2016, 7, 50. [Google Scholar] [CrossRef]
  21. Yuan, X.; Larsson, C.; Xu, D. Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: Old actors and new players. Oncogene 2019, 38, 6172–6183. [Google Scholar] [CrossRef] [Green Version]
  22. Okamoto, K.; Seimiya, H. Revisiting telomere shortening in cancer. Cells 2019, 8, 107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Ulaner, G.A.; Hu, J.F.; Vu, T.H.; Giudice, L.C.; Hoffman, A.R. Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res. 1998, 58, 4168–4172. [Google Scholar] [PubMed]
  24. Ulaner, G.A.; Hu, J.F.; Vu, T.H.; Giudice, L.C.; Hoffman, A.R. Tissue-specific alternate splicing of human telomerase reverse transcriptase (hTERT) influences telomere lengths during human development. Int. J. Cancer 2001, 91, 644–649. [Google Scholar] [CrossRef]
  25. Kang, S.S.; Kwon, T.; Kwon, D.Y.; Do, S.I. Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. J. Biol. Chem. 1999, 274, 13085–13090. [Google Scholar] [CrossRef] [Green Version]
  26. Bellon, M.; Nicot, C. Central role of PI3K in transcriptional activation of hTERT in HTLV-I-infected cells. Blood 2008, 112, 2946–2955. [Google Scholar] [CrossRef] [Green Version]
  27. Heeg, S.; Hirt, N.; Queisser, A.; Schmieg, H.; Thaler, M.; Kunert, H.; Quante, M.; Goessel, G.; von Werder, A.; Harder, J.; et al. EGFR overexpression induces activation of telomerase via PI3K/AKT-mediated phosphorylation and transcriptional regulation through Hif1-alpha in a cellular model of oral-esophageal carcinogenesis. Cancer Sci. 2011, 102, 351–360. [Google Scholar] [CrossRef]
  28. Yang, K.; Zheng, D.; Deng, X.; Bai, L.; Xu, Y.; Cong, Y.S. Lysophosphatidic acid activates telomerase in ovarian cancer cells through hypoxia-inducible factor-1alpha and the PI3K pathway. J. Cell Biochem. 2008, 105, 1194–1201. [Google Scholar] [CrossRef]
  29. Pestana, A.; Vinagre, J.; Sobrinho-Simoes, M.; Soares, P. TERT biology and function in cancer: Beyond immortalisation. J. Mol. Endocrinol. 2017, 58, R129–R146. [Google Scholar] [CrossRef]
  30. Klingelhutz, A.J.; Foster, S.A.; McDougall, J.K. Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature 1996, 380, 79–82. [Google Scholar] [CrossRef]
  31. Zhang, A.; Zheng, C.; Lindvall, C.; Hou, M.; Ekedahl, J.; Lewensohn, R.; Yan, Z.; Yang, X.; Henriksson, M.; Blennow, E.; et al. Frequent amplification of the telomerase reverse transcriptase gene in human tumors. Cancer Res. 2000, 60, 6230–6235. [Google Scholar]
  32. Oh, S.T.; Kyo, S.; Laimins, L.A. Telomerase activation by human papillomavirus type 16 E6 protein: Induction of human telomerase reverse transcriptase expression through Myc and GC-rich Sp1 binding sites. J. Virol. 2001, 75, 5559–5566. [Google Scholar] [CrossRef] [Green Version]
  33. Veldman, T.; Horikawa, I.; Barrett, J.C.; Schlegel, R. Transcriptional activation of the telomerase hTERT gene by human papillomavirus type 16 E6 oncoprotein. J. Virol. 2001, 75, 4467–4472. [Google Scholar] [CrossRef] [Green Version]
  34. Paterlini-Brechot, P.; Saigo, K.; Murakami, Y.; Chami, M.; Gozuacik, D.; Mugnier, C.; Lagorce, D.; Brechot, C. Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene 2003, 22, 3911–3916. [Google Scholar] [CrossRef]
  35. Peifer, M.; Hertwig, F.; Roels, F.; Dreidax, D.; Gartlgruber, M.; Menon, R.; Kramer, A.; Roncaioli, J.L.; Sand, F.; Heuckmann, J.M.; et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 2015, 526, 700–704. [Google Scholar] [CrossRef]
  36. Vinothkumar, V.; Arunkumar, G.; Revathidevi, S.; Arun, K.; Manikandan, M.; Rao, A.K.; Rajkumar, K.S.; Ajay, C.; Rajaraman, R.; Ramani, R.; et al. Erratum to: TERT promoter hot spot mutations are frequent in Indian cervical and oral squamous cell carcinomas. Tumour Biol. 2016, 37, 7005. [Google Scholar] [CrossRef] [Green Version]
  37. Annunziata, C.; Pezzuto, F.; Greggi, S.; Ionna, F.; Losito, S.; Botti, G.; Buonaguro, L.; Buonaguro, F.M.; Tornesello, M.L. Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma. Int. J. Cancer 2018, 143, 1153–1161. [Google Scholar] [CrossRef] [Green Version]
  38. Gaspar, T.B.; Sa, A.; Lopes, J.M.; Sobrinho-Simoes, M.; Soares, P.; Vinagre, J. Telomere maintenance mechanisms in cancer. Genes 2018, 9, 241. [Google Scholar] [CrossRef] [Green Version]
  39. Jafri, M.A.; Ansari, S.A.; Alqahtani, M.H.; Shay, J.W. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med. 2016, 69, 8. [Google Scholar] [CrossRef] [Green Version]
  40. Arita, H.; Narita, Y.; Takami, H.; Fukushima, S.; Matsushita, Y.; Yoshida, A.; Miyakita, Y.; Ohno, M.; Shibui, S.; Ichimura, K. TERT promoter mutations rather than methylation are the main mechanism for TERT upregulation in adult gliomas. Acta Neuropathol. 2013, 126, 939–941. [Google Scholar] [CrossRef]
  41. Guilleret, I.; Yan, P.; Grange, F.; Braunschweig, R.; Bosman, F.T.; Benhattar, J. Hypermethylation of the human telomerase catalytic subunit (hTERT) gene correlates with telomerase activity. Int. J. Cancer 2002, 101, 335–341. [Google Scholar] [CrossRef]
  42. Guilleret, I.; Benhattar, J. Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres. Exp. Cell Res. 2003, 289, 326–334. [Google Scholar] [CrossRef]
  43. Renaud, S.; Loukinov, D.; Abdullaev, Z.; Guilleret, I.; Bosman, F.T.; Lobanenkov, V.; Benhattar, J. Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene. Nucleic Acids Res. 2007, 35, 1245–1256. [Google Scholar] [CrossRef] [Green Version]
  44. Renaud, S.; Loukinov, D.; Bosman, F.T.; Lobanenkov, V.; Benhattar, J. CTCF binds the proximal exonic region of hTERT and inhibits its transcription. Nucleic Acids Res. 2005, 33, 6850–6860. [Google Scholar] [CrossRef] [PubMed]
  45. De Wilde, J.; Kooter, J.M.; Overmeer, R.M.; Claassen-Kramer, D.; Meijer, C.J.; Snijders, P.J.; Steenbergen, R.D. hTERT promoter activity and CpG methylation in HPV-induced carcinogenesis. BMC Cancer 2010, 10, 271. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Lewis, K.A.; Tollefsbol, T.O. Regulation of the telomerase reverse transcriptase subunit through epigenetic mechanisms. Front. Genet. 2016, 7, 83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Ko, E.; Seo, H.W.; Jung, E.S.; Kim, B.H.; Jung, G. The TERT promoter SNP rs2853669 decreases E2F1 transcription factor binding and increases mortality and recurrence risks in liver cancer. Oncotarget 2016, 7, 684–699. [Google Scholar] [CrossRef] [PubMed]
  48. Yuan, X.; Xu, D. Telomerase reverse transcriptase (TERT) in action: Cross-talking with epigenetics. Int. J. Mol. Sci. 2019, 20, 3338. [Google Scholar] [CrossRef] [Green Version]
  49. Horn, S.; Figl, A.; Rachakonda, P.S.; Fischer, C.; Sucker, A.; Gast, A.; Kadel, S.; Moll, I.; Nagore, E.; Hemminki, K.; et al. TERT promoter mutations in familial and sporadic melanoma. Science 2013, 339, 959–961. [Google Scholar] [CrossRef] [Green Version]
  50. Huang, F.W.; Hodis, E.; Xu, M.J.; Kryukov, G.V.; Chin, L.; Garraway, L.A. Highly recurrent TERT promoter mutations in human melanoma. Science 2013, 339, 957–959. [Google Scholar] [CrossRef] [Green Version]
  51. Andres-Lencina, J.J.; Rachakonda, S.; Garcia-Casado, Z.; Srinivas, N.; Skorokhod, A.; Requena, C.; Soriano, V.; Kumar, R.; Nagore, E. TERT promoter mutation subtypes and survival in stage I and II melanoma patients. Int. J. Cancer 2018, 144, 1027–1036. [Google Scholar] [CrossRef] [PubMed]
  52. Vinagre, J.; Almeida, A.; Populo, H.; Batista, R.; Lyra, J.; Pinto, V.; Coelho, R.; Celestino, R.; Prazeres, H.; Lima, L.; et al. Frequency of TERT promoter mutations in human cancers. Nat. Commun. 2013, 4, 2185. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Arita, H.; Narita, Y.; Fukushima, S.; Tateishi, K.; Matsushita, Y.; Yoshida, A.; Miyakita, Y.; Ohno, M.; Collins, V.P.; Kawahara, N.; et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol. 2013, 126, 267–276. [Google Scholar] [CrossRef] [PubMed]
  54. Huang, F.W.; Bielski, C.M.; Rinne, M.L.; Hahn, W.C.; Sellers, W.R.; Stegmeier, F.; Garraway, L.A.; Kryukov, G.V. TERT promoter mutations and monoallelic activation of TERT in cancer. Oncogenesis 2015, 4, e176. [Google Scholar] [CrossRef] [Green Version]
  55. Griewank, K.G.; Murali, R.; Schilling, B.; Schimming, T.; Moller, I.; Moll, I.; Schwamborn, M.; Sucker, A.; Zimmer, L.; Schadendorf, D.; et al. TERT promoter mutations are frequent in cutaneous basal cell carcinoma and squamous cell carcinoma. PLoS ONE 2013, 8, e80354. [Google Scholar] [CrossRef]
  56. Rachakonda, P.S.; Hosen, I.; de Verdier, P.J.; Fallah, M.; Heidenreich, B.; Ryk, C.; Wiklund, N.P.; Steineck, G.; Schadendorf, D.; Hemminki, K.; et al. TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism. Proc. Natl. Acad. Sci. USA 2013, 110, 17426–17431. [Google Scholar] [CrossRef] [Green Version]
  57. Huang, D.S.; Wang, Z.; He, X.J.; Diplas, B.H.; Yang, R.; Killela, P.J.; Meng, Q.; Ye, Z.Y.; Wang, W.; Jiang, X.T.; et al. Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur. J. Cancer 2015, 51, 969–976. [Google Scholar] [CrossRef] [Green Version]
  58. Johanns, T.M.; Fu, Y.; Kobayashi, D.K.; Mei, Y.; Dunn, I.F.; Mao, D.D.; Kim, A.H.; Dunn, G.P. High incidence of TERT mutation in brain tumor cell lines. Brain Tumor Pathol. 2016, 33, 222–227. [Google Scholar] [CrossRef] [Green Version]
  59. Li, Y.; Zhou, Q.L.; Sun, W.; Chandrasekharan, P.; Cheng, H.S.; Ying, Z.; Lakshmanan, M.; Raju, A.; Tenen, D.G.; Cheng, S.Y.; et al. Non-canonical NF-kappaB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation. Nat. Cell Biol. 2015, 17, 1327–1338. [Google Scholar] [CrossRef]
  60. Chen, C.; Han, S.; Meng, L.; Li, Z.; Zhang, X.; Wu, A. TERT promoter mutations lead to high transcriptional activity under hypoxia and temozolomide treatment and predict poor prognosis in gliomas. PLoS ONE 2014, 9, e100297. [Google Scholar] [CrossRef] [Green Version]
  61. Hosen, I.; Rachakonda, P.S.; Heidenreich, B.; de Verdier, P.J.; Ryk, C.; Steineck, G.; Hemminki, K.; Kumar, R. Mutations in TERT promoter and FGFR3 and telomere length in bladder cancer. Int. J. Cancer 2015, 137, 1621–1629. [Google Scholar] [CrossRef] [PubMed]
  62. Nault, J.C.; Mallet, M.; Pilati, C.; Calderaro, J.; Bioulac-Sage, P.; Laurent, C.; Laurent, A.; Cherqui, D.; Balabaud, C.; Zucman-Rossi, J. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat. Commun. 2013, 4, 2218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Yang, X.; Guo, X.; Chen, Y.; Chen, G.; Ma, Y.; Huang, K.; Zhang, Y.; Zhao, Q.; Winkler, C.A.; An, P.; et al. Telomerase reverse transcriptase promoter mutations in hepatitis B virus-associated hepatocellular carcinoma. Oncotarget 2016, 7, 27838–27847. [Google Scholar] [CrossRef] [Green Version]
  64. Park, C.K.; Lee, S.H.; Kim, J.Y.; Kim, J.E.; Kim, T.M.; Lee, S.T.; Choi, S.H.; Park, S.H.; Kim, I.H. Expression level of hTERT is regulated by somatic mutation and common single nucleotide polymorphism at promoter region in glioblastoma. Oncotarget 2014, 5, 3399–3407. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Spiegl-Kreinecker, S.; Lotsch, D.; Ghanim, B.; Pirker, C.; Mohr, T.; Laaber, M.; Weis, S.; Olschowski, A.; Webersinke, G.; Pichler, J.; et al. Prognostic quality of activating TERT promoter mutations in glioblastoma: Interaction with the rs2853669 polymorphism and patient age at diagnosis. Neuro Oncol. 2015, 17, 1231–1240. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Chiba, K.; Lorbeer, F.K.; Shain, A.H.; McSwiggen, D.T.; Schruf, E.; Oh, A.; Ryu, J.; Darzacq, X.; Bastian, B.C.; Hockemeyer, D. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science 2017, 357, 1416–1420. [Google Scholar] [CrossRef] [Green Version]
  67. Li, C.; Wu, S.; Wang, H.; Bi, X.; Yang, Z.; Du, Y.; He, L.; Cai, Z.; Wang, J.; Fan, Z. The C228T mutation of TERT promoter frequently occurs in bladder cancer stem cells and contributes to tumorigenesis of bladder cancer. Oncotarget 2015, 6, 19542–19551. [Google Scholar] [CrossRef] [Green Version]
  68. Sizemore, G.M.; Pitarresi, J.R.; Balakrishnan, S.; Ostrowski, M.C. The ETS family of oncogenic transcription factors in solid tumours. Nat. Rev. Cancer 2017, 17, 337–351. [Google Scholar] [CrossRef]
  69. Bell, R.J.; Rube, H.T.; Kreig, A.; Mancini, A.; Fouse, S.D.; Nagarajan, R.P.; Choi, S.; Hong, C.; He, D.; Pekmezci, M.; et al. Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science 2015, 348, 1036–1039. [Google Scholar] [CrossRef] [Green Version]
  70. Akincilar, S.C.; Khattar, E.; Boon, P.L.; Unal, B.; Fullwood, M.J.; Tergaonkar, V. Long-range chromatin interactions drive mutant tert promoter activation. Cancer Discov. 2016, 6, 1276–1291. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. Mancini, A.; Xavier-Magalhaes, A.; Woods, W.S.; Nguyen, K.T.; Amen, A.M.; Hayes, J.L.; Fellmann, C.; Gapinske, M.; McKinney, A.M.; Hong, C.; et al. Disruption of the beta1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner. Cancer Cell 2018, 34, 513–528. [Google Scholar] [CrossRef] [Green Version]
  72. Thompson, C.C.; Brown, T.A.; McKnight, S.L. Convergence of Ets-and notch-related structural motifs in a heteromeric DNA binding complex. Science 1991, 253, 762–768. [Google Scholar] [CrossRef] [PubMed]
  73. Oikawa, T.; Yamada, T. Molecular biology of the Ets family of transcription factors. Gene 2003, 303, 11–34. [Google Scholar] [CrossRef]
  74. LaMarco, K.; Thompson, C.C.; Byers, B.P.; Walton, E.M.; McKnight, S.L. Identification of Ets- and notch-related subunits in GA binding protein. Science 1991, 253, 789–792. [Google Scholar] [CrossRef] [PubMed]
  75. Stern, J.L.; Theodorescu, D.; Vogelstein, B.; Papadopoulos, N.; Cech, T.R. Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers. Genes Dev. 2015, 29, 2219–2224. [Google Scholar] [CrossRef] [Green Version]
  76. Stern, J.L.; Paucek, R.D.; Huang, F.W.; Ghandi, M.; Nwumeh, R.; Costello, J.C.; Cech, T.R. Allele-specific DNA methylation and its interplay with repressive histone marks at promoter-mutant tert genes. Cell Rep. 2017, 21, 3700–3707. [Google Scholar] [CrossRef] [Green Version]
  77. Killela, P.J.; Reitman, Z.J.; Jiao, Y.; Bettegowda, C.; Agrawal, N.; Diaz, L.A., Jr.; Friedman, A.H.; Friedman, H.; Gallia, G.L.; Giovanella, B.C.; et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl. Acad. Sci. USA 2013, 110, 6021–6026. [Google Scholar] [CrossRef] [Green Version]
  78. Liu, X.; Wu, G.; Shan, Y.; Hartmann, C.; von Deimling, A.; Xing, M. Highly prevalent TERT promoter mutations in bladder cancer and glioblastoma. Cell Cycle 2013, 12, 1637–1638. [Google Scholar] [CrossRef] [Green Version]
  79. Pekmezci, M.; Rice, T.; Molinaro, A.M.; Walsh, K.M.; Decker, P.A.; Hansen, H.; Sicotte, H.; Kollmeyer, T.M.; McCoy, L.S.; Sarkar, G.; et al. Adult infiltrating gliomas with WHO 2016 integrated diagnosis: Additional prognostic roles of ATRX and TERT. Acta Neuropathol. 2017, 133, 1001–1016. [Google Scholar] [CrossRef]
  80. Eckel-Passow, J.E.; Lachance, D.H.; Molinaro, A.M.; Walsh, K.M.; Decker, P.A.; Sicotte, H.; Pekmezci, M.; Rice, T.; Kosel, M.L.; Smirnov, I.V.; et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N. Engl. J. Med. 2015, 372, 2499–2508. [Google Scholar] [CrossRef] [Green Version]
  81. Simon, M.; Hosen, I.; Gousias, K.; Rachakonda, S.; Heidenreich, B.; Gessi, M.; Schramm, J.; Hemminki, K.; Waha, A.; Kumar, R. TERT promoter mutations: A novel independent prognostic factor in primary glioblastomas. Neuro Oncol. 2015, 17, 45–52. [Google Scholar] [CrossRef] [PubMed]
  82. Arita, H.; Yamasaki, K.; Matsushita, Y.; Nakamura, T.; Shimokawa, A.; Takami, H.; Tanaka, S.; Mukasa, A.; Shirahata, M.; Shimizu, S.; et al. A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta Neuropathol. Commun. 2016, 4, 79. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Yang, P.; Cai, J.; Yan, W.; Zhang, W.; Wang, Y.; Chen, B.; Li, G.; Li, S.; Wu, C.; Yao, K.; et al. Classification based on mutations of TERT promoter and IDH characterizes subtypes in grade II/III gliomas. Neuro Oncol. 2016, 18, 1099–1108. [Google Scholar] [CrossRef] [Green Version]
  84. Mosrati, M.A.; Malmstrom, A.; Lysiak, M.; Krysztofiak, A.; Hallbeck, M.; Milos, P.; Hallbeck, A.L.; Bratthall, C.; Strandeus, M.; Stenmark-Askmalm, M.; et al. TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma. Oncotarget 2015, 6, 16663–16673. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Batista, R.; Cruvinel-Carloni, A.; Vinagre, J.; Peixoto, J.; Catarino, T.A.; Campanella, N.C.; Menezes, W.; Becker, A.P.; de Almeida, G.C.; Matsushita, M.M.; et al. The prognostic impact of TERT promoter mutations in glioblastomas is modified by the rs2853669 single nucleotide polymorphism. Int. J. Cancer 2016, 139, 414–423. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Williams, E.A.; Miller, J.J.; Tummala, S.S.; Penson, T.; Iafrate, A.J.; Juratli, T.A.; Cahill, D.P. TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations. Acta Neuropathol. Commun. 2018, 6, 106. [Google Scholar] [CrossRef] [Green Version]
  87. Griewank, K.G.; Murali, R.; Schilling, B.; Scholz, S.; Sucker, A.; Song, M.; Susskind, D.; Grabellus, F.; Zimmer, L.; Hillen, U.; et al. TERT promoter mutations in ocular melanoma distinguish between conjunctival and uveal tumours. Br. J. Cancer 2013, 109, 497–501. [Google Scholar] [CrossRef] [Green Version]
  88. Heidenreich, B.; Nagore, E.; Rachakonda, P.S.; Garcia-Casado, Z.; Requena, C.; Traves, V.; Becker, J.; Soufir, N.; Hemminki, K.; Kumar, R. Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma. Nat. Commun. 2014, 5, 3401. [Google Scholar] [CrossRef]
  89. Populo, H.; Boaventura, P.; Vinagre, J.; Batista, R.; Mendes, A.; Caldas, R.; Pardal, J.; Azevedo, F.; Honavar, M.; Guimaraes, I.; et al. TERT promoter mutations in skin cancer: The effects of sun exposure and X-irradiation. J. Invest. Dermatol. 2014, 134, 2251–2257. [Google Scholar] [CrossRef] [Green Version]
  90. Scott, G.A.; Laughlin, T.S.; Rothberg, P.G. Mutations of the TERT promoter are common in basal cell carcinoma and squamous cell carcinoma. Mod. Pathol. 2014, 27, 516–523. [Google Scholar] [CrossRef] [Green Version]
  91. Ofner, R.; Ritter, C.; Heidenreich, B.; Kumar, R.; Ugurel, S.; Schrama, D.; Becker, J.C. Distribution of TERT promoter mutations in primary and metastatic melanomas in Austrian patients. J. Cancer Res. Clin. Oncol. 2017, 143, 613–617. [Google Scholar] [CrossRef] [PubMed]
  92. Nguyen, D.; Taheri, D.; Springer, S.; Cowan, M.; Guner, G.; Mendoza Rodriguez, M.A.; Wang, Y.; Kinde, I.; VandenBussche, C.J.; Olson, M.T.; et al. High prevalence of TERT promoter mutations in micropapillary urothelial carcinoma. Virchows Arch. 2016, 469, 427–434. [Google Scholar] [CrossRef] [Green Version]
  93. Cowan, M.; Springer, S.; Nguyen, D.; Taheri, D.; Guner, G.; Rodriguez, M.A.; Wang, Y.; Kinde, I.; VandenBussche, C.J.; Olson, M.T.; et al. High prevalence of TERT promoter mutations in primary squamous cell carcinoma of the urinary bladder. Mod. Pathol. 2016, 29, 511–515. [Google Scholar] [CrossRef]
  94. Allory, Y.; Beukers, W.; Sagrera, A.; Flandez, M.; Marques, M.; Marquez, M.; van der Keur, K.A.; Dyrskjot, L.; Lurkin, I.; Vermeij, M.; et al. Telomerase reverse transcriptase promoter mutations in bladder cancer: High frequency across stages, detection in urine, and lack of association with outcome. Eur. Urol. 2014, 65, 360–366. [Google Scholar] [CrossRef] [Green Version]
  95. Pezzuto, F.; Izzo, F.; Buonaguro, L.; Annunziata, C.; Tatangelo, F.; Botti, G.; Buonaguro, F.M.; Tornesello, M.L. Tumor specific mutations in TERT promoter and CTNNB1 gene in hepatitis B and hepatitis C related hepatocellular carcinoma. Oncotarget 2016, 7, 54253–54262. [Google Scholar] [CrossRef] [Green Version]
  96. Chen, Y.L.; Jeng, Y.M.; Chang, C.N.; Lee, H.J.; Hsu, H.C.; Lai, P.L.; Yuan, R.H. TERT promoter mutation in resectable hepatocellular carcinomas: A strong association with hepatitis C infection and absence of hepatitis B infection. Int. J. Surg. 2014, 12, 659–665. [Google Scholar] [CrossRef] [Green Version]
  97. Cevik, D.; Yildiz, G.; Ozturk, M. Common telomerase reverse transcriptase promoter mutations in hepatocellular carcinomas from different geographical locations. World J. Gastroenterol. 2015, 21, 311–317. [Google Scholar] [CrossRef] [PubMed]
  98. Liu, T.; Wang, N.; Cao, J.; Sofiadis, A.; Dinets, A.; Zedenius, J.; Larsson, C.; Xu, D. The age-and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas. Oncogene 2014, 33, 4978–4984. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Liu, X.; Qu, S.; Liu, R.; Sheng, C.; Shi, X.; Zhu, G.; Murugan, A.K.; Guan, H.; Yu, H.; Wang, Y.; et al. TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J. Clin. Endocrinol. Metab. 2014, 9, E1130–E1136. [Google Scholar] [CrossRef] [Green Version]
  100. Landa, I.; Ganly, I.; Chan, T.A.; Mitsutake, N.; Matsuse, M.; Ibrahimpasic, T.; Ghossein, R.A.; Fagin, J.A. Frequent somatic TERT promoter mutations in thyroid cancer: Higher prevalence in advanced forms of the disease. J. Clin. Endocrinol. Metab. 2013, 98, E1562–E1566. [Google Scholar] [CrossRef] [Green Version]
  101. Melo, M.; da Rocha, A.G.; Vinagre, J.; Batista, R.; Peixoto, J.; Tavares, C.; Celestino, R.; Almeida, A.; Salgado, C.; Eloy, C.; et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J. Clin. Endocrinol. Metab. 2014, 99, E754–E765. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Muzza, M.; Colombo, C.; Rossi, S.; Tosi, D.; Cirello, V.; Perrino, M.; De Leo, S.; Magnani, E.; Pignatti, E.; Vigo, B.; et al. Telomerase in differentiated thyroid cancer: Promoter mutations, expression and localization. Mol. Cell Endocrinol. 2015, 399, 288–295. [Google Scholar] [CrossRef] [PubMed]
  103. George, J.R.; Henderson, Y.C.; Williams, M.D.; Roberts, D.B.; Hei, H.; Lai, S.Y.; Clayman, G.L. Association of TERT promoter mutation, but not braf mutation, with increased mortality in PTC. J. Clin. Endocrinol. Metab. 2015, 100, E1550–E1559. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Shi, X.; Liu, R.; Qu, S.; Zhu, G.; Bishop, J.; Liu, X.; Sun, H.; Shan, Z.; Wang, E.; Luo, Y.; et al. Association of TERT promoter mutation 1,295,228 C>T with BRAF V600E mutation, older patient age, and distant metastasis in anaplastic thyroid cancer. J. Clin. Endocrinol. Metab. 2015, 100, E632–E637. [Google Scholar] [CrossRef] [Green Version]
  105. Bae, J.S.; Kim, Y.; Jeon, S.; Kim, S.H.; Kim, T.J.; Lee, S.; Kim, M.H.; Lim, D.J.; Lee, Y.S.; Jung, C.K. Clinical utility of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of the BRAF V600E mutation. Diagn. Pathol. 2016, 11, 21. [Google Scholar] [CrossRef] [Green Version]
  106. Song, Y.S.; Lim, J.A.; Choi, H.; Won, J.K.; Moon, J.H.; Cho, S.W.; Lee, K.E.; Park, Y.J.; Yi, K.H.; Park, D.J.; et al. Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients. Cancer 2016, 122, 1370–1379. [Google Scholar] [CrossRef]
  107. Akincilar, S.C.; Low, K.C.; Liu, C.Y.; Yan, T.D.; Oji, A.; Ikawa, M.; Li, S.; Tergaonkar, V. Quantitative assessment of telomerase components in cancer cell lines. FEBS Lett. 2015, 589, 974–984. [Google Scholar] [CrossRef]
  108. Liu, X.; Bishop, J.; Shan, Y.; Pai, S.; Liu, D.; Murugan, A.K.; Sun, H.; El-Naggar, A.K.; Xing, M. Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr. Relat. Cancer 2013, 20, 603–610. [Google Scholar] [CrossRef] [Green Version]
  109. Chiba, K.; Johnson, J.Z.; Vogan, J.M.; Wagner, T.; Boyle, J.M.; Hockemeyer, D. Cancer-associated TERT promoter mutations abrogate telomerase silencing. Elife 2015, 4, e07918. [Google Scholar] [CrossRef]
  110. Karsy, M.; Guan, J.; Cohen, A.L.; Jensen, R.L.; Colman, H. New Molecular Considerations for Glioma: IDH, ATRX, BRAF, TERT, H3 K27M. Curr. Neurol. Neurosci. Rep. 2017, 17, 19. [Google Scholar] [CrossRef]
  111. Nonoguchi, N.; Ohta, T.; Oh, J.E.; Kim, Y.H.; Kleihues, P.; Ohgaki, H. TERT promoter mutations in primary and secondary glioblastomas. Acta Neuropathol. 2013, 126, 931–937. [Google Scholar] [CrossRef] [PubMed]
  112. Heidenreich, B.; Rachakonda, P.S.; Hosen, I.; Volz, F.; Hemminki, K.; Weyerbrock, A.; Kumar, R. TERT promoter mutations and telomere length in adult malignant gliomas and recurrences. Oncotarget 2015, 6, 10617–10633. [Google Scholar] [CrossRef] [Green Version]
  113. Hakin-Smith, V.; Jellinek, D.A.; Levy, D.; Carroll, T.; Teo, M.; Timperley, W.R.; McKay, M.J.; Reddel, R.R.; Royds, J.A. Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme. Lancet 2003, 361, 836–838. [Google Scholar] [CrossRef]
  114. Zhang, Z.Y.; Chan, A.K.; Ding, X.J.; Qin, Z.Y.; Hong, C.S.; Chen, L.C.; Zhang, X.; Zhao, F.P.; Wang, Y.; Wang, Y.; et al. TERT promoter mutations contribute to IDH mutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas. Oncotarget 2015, 6, 24871–24883. [Google Scholar] [CrossRef] [PubMed]
  115. Rachakonda, S.; Kong, H.; Srinivas, N.; Garcia-Casado, Z.; Requena, C.; Fallah, M.; Heidenreich, B.; Planelles, D.; Traves, V.; Schadendorf, D.; et al. Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk. Genes Chromosomes Cancer 2018, 57, 564–572. [Google Scholar] [CrossRef] [PubMed]
  116. Nagore, E.; Heidenreich, B.; Rachakonda, S.; Garcia-Casado, Z.; Requena, C.; Soriano, V.; Frank, C.; Traves, V.; Quecedo, E.; Sanjuan-Gimenez, J.; et al. TERT promoter mutations in melanoma survival. Int. J. Cancer 2016, 139, 75–84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Hayward, N.K.; Wilmott, J.S.; Waddell, N.; Johansson, P.A.; Field, M.A.; Nones, K.; Patch, A.M.; Kakavand, H.; Alexandrov, L.B.; Burke, H.; et al. Whole-genome landscapes of major melanoma subtypes. Nature 2017, 545, 175–180. [Google Scholar] [CrossRef]
  118. Wang, K.; Liu, T.; Ge, N.; Liu, L.; Yuan, X.; Liu, J.; Kong, F.; Wang, C.; Ren, H.; Yan, K.; et al. TERT promoter mutations are associated with distant metastases in upper tract urothelial carcinomas and serve as urinary biomarkers detected by a sensitive castPCR. Oncotarget 2014, 5, 12428–12439. [Google Scholar] [CrossRef] [Green Version]
  119. Borah, S.; Xi, L.; Zaug, A.J.; Powell, N.M.; Dancik, G.M.; Cohen, S.B.; Costello, J.C.; Theodorescu, D.; Cech, T.R. Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science 2015, 347, 1006–1010. [Google Scholar] [CrossRef] [Green Version]
  120. Pilati, C.; Letouze, E.; Nault, J.C.; Imbeaud, S.; Boulai, A.; Calderaro, J.; Poussin, K.; Franconi, A.; Couchy, G.; Morcrette, G.; et al. Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell 2014, 25, 428–441. [Google Scholar] [CrossRef] [Green Version]
  121. Totoki, Y.; Tatsuno, K.; Covington, K.R.; Ueda, H.; Creighton, C.J.; Kato, M.; Tsuji, S.; Donehower, L.A.; Slagle, B.L.; Nakamura, H.; et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet. 2014, 46, 1267–1273. [Google Scholar] [CrossRef] [PubMed]
  122. Kawai-Kitahata, F.; Asahina, Y.; Tanaka, S.; Kakinuma, S.; Murakawa, M.; Nitta, S.; Watanabe, T.; Otani, S.; Taniguchi, M.; Goto, F.; et al. Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. J. Gastroenterol. 2016, 51, 473–486. [Google Scholar] [CrossRef] [PubMed]
  123. Sung, W.K.; Zheng, H.; Li, S.; Chen, R.; Liu, X.; Li, Y.; Lee, N.P.; Lee, W.H.; Ariyaratne, P.N.; Tennakoon, C.; et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat. Genet. 2012, 44, 765–769. [Google Scholar] [CrossRef]
  124. Bonilla Guerrero, R.; Roberts, L.R. The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma. J. Hepatol. 2005, 42, 760–777. [Google Scholar] [CrossRef] [PubMed]
  125. Vartanian, J.P.; Guetard, D.; Henry, M.; Wain-Hobson, S. Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and precancerous lesions. Science 2008, 320, 230–233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Henderson, S.; Chakravarthy, A.; Su, X.; Boshoff, C.; Fenton, T.R. APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. Cell Rep. 2014, 7, 1833–1841. [Google Scholar] [CrossRef] [Green Version]
  127. Alexandrov, L.B.; Nik-Zainal, S.; Wedge, D.C.; Aparicio, S.A.; Behjati, S.; Biankin, A.V.; Bignell, G.R.; Bolli, N.; Borg, A.; Borresen-Dale, A.L.; et al. Signatures of mutational processes in human cancer. Nature 2013, 500, 415–421. [Google Scholar] [CrossRef] [Green Version]
  128. Wang, H.Y.; Park, S.; Kim, S.; Lee, D.; Kim, G.; Kim, Y.; Park, K.H.; Lee, H. Use of hTERT and HPV E6/E7 mRNA RT-qPCR TaqMan assays in combination for diagnosing high-grade cervical lesions and malignant tumors. Am. J. Clin. Pathol. 2015, 143, 344–351. [Google Scholar] [CrossRef] [Green Version]
  129. Van Doorslaer, K.; Burk, R.D. Association between hTERT activation by HPV E6 proteins and oncogenic risk. Virology 2012, 433, 216–219. [Google Scholar] [CrossRef] [Green Version]
  130. Hsu, C.P.; Hsu, N.Y.; Lee, L.W.; Ko, J.L. Ets2 binding site single nucleotide polymorphism at the hTERT gene promoter--effect on telomerase expression and telomere length maintenance in non-small cell lung cancer. Eur. J. Cancer 2006, 42, 1466–1474. [Google Scholar] [CrossRef]
  131. Shen, N.; Lu, Y.; Wang, X.; Peng, J.; Zhu, Y.; Cheng, L. Association between rs2853669 in TERT gene and the risk and prognosis of human cancer: A systematic review and meta-analysis. Oncotarget 2017, 8, 50864–50872. [Google Scholar] [CrossRef] [PubMed]
  132. Wu, R.C.; Ayhan, A.; Maeda, D.; Kim, K.R.; Clarke, B.A.; Shaw, P.; Chui, M.H.; Rosen, B.; Shih Ie, M.; Wang, T.L. Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynaecological malignancy. J. Pathol. 2014, 232, 473–481. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Chan, K.; Roberts, S.A.; Klimczak, L.J.; Sterling, J.F.; Saini, N.; Malc, E.P.; Kim, J.; Kwiatkowski, D.J.; Fargo, D.C.; Mieczkowski, P.A.; et al. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat. Genet. 2015, 47, 1067–1072. [Google Scholar] [CrossRef] [PubMed]
  134. Vartanian, J.P.; Henry, M.; Marchio, A.; Suspene, R.; Aynaud, M.M.; Guetard, D.; Cervantes-Gonzalez, M.; Battiston, C.; Mazzaferro, V.; Pineau, P.; et al. Massive APOBEC3 editing of hepatitis B viral DNA in cirrhosis. PLoS Pathog. 2010, 6, e1000928. [Google Scholar] [CrossRef]
  135. Singh, A.M.; Reynolds, D.; Cliff, T.; Ohtsuka, S.; Mattheyses, A.L.; Sun, Y.; Menendez, L.; Kulik, M.; Dalton, S. Signaling network crosstalk in human pluripotent cells: A Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell 2012, 10, 312–326. [Google Scholar] [CrossRef] [Green Version]
  136. Park, J.I.; Venteicher, A.S.; Hong, J.Y.; Choi, J.; Jun, S.; Shkreli, M.; Chang, W.; Meng, Z.; Cheung, P.; Ji, H.; et al. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 2009, 460, 66–72. [Google Scholar] [CrossRef] [Green Version]
  137. Liu, Z.; Li, Q.; Li, K.; Chen, L.; Li, W.; Hou, M.; Liu, T.; Yang, J.; Lindvall, C.; Bjorkholm, M.; et al. Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells. Oncogene 2013, 32, 4203–4213. [Google Scholar] [CrossRef] [Green Version]
  138. Koh, C.M.; Khattar, E.; Leow, S.C.; Liu, C.Y.; Muller, J.; Ang, W.X.; Li, Y.; Franzoso, G.; Li, S.; Guccione, E.; et al. Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity. J. Clin. Invest. 2015, 125, 2109–2122. [Google Scholar] [CrossRef] [Green Version]
  139. Tang, B.; Xie, R.; Qin, Y.; Xiao, Y.F.; Yong, X.; Zheng, L.; Dong, H.; Yang, S.M. Human telomerase reverse transcriptase (hTERT) promotes gastric cancer invasion through cooperating with c-Myc to upregulate heparanase expression. Oncotarget 2016, 7, 11364–11379. [Google Scholar] [CrossRef]
  140. Ghosh, A.; Saginc, G.; Leow, S.C.; Khattar, E.; Shin, E.M.; Yan, T.D.; Wong, M.; Zhang, Z.; Li, G.; Sung, W.K.; et al. Tergaonkar, Telomerase directly regulates NF-kappaB-dependent transcription. Nat. Cell Biol. 2012, 14, 1270–1281. [Google Scholar] [CrossRef]
  141. Ding, D.; Xi, P.; Zhou, J.; Wang, M.; Cong, Y.S. Human telomerase reverse transcriptase regulates MMP expression independently of telomerase activity via NF-kappaB-dependent transcription. FASEB J. 2013, 27, 4375–4383. [Google Scholar] [CrossRef]
  142. Li, Y.; Tergaonkar, V. Noncanonical functions of telomerase: Implications in telomerase-targeted cancer therapies. Cancer Res. 2014, 74, 1639–1644. [Google Scholar] [CrossRef] [Green Version]
  143. Yu, J.; Yuan, X.; Sjoholm, L.; Liu, T.; Kong, F.; Ekstrom, T.J.; Bjorkholm, M.; Xu, D. Telomerase reverse transcriptase regulates DNMT3B expression/aberrant DNA methylation phenotype and AKT activation in hepatocellular carcinoma. Cancer Lett. 2018, 434, 33–41. [Google Scholar] [CrossRef] [PubMed]
  144. Masutomi, K.; Possemato, R.; Wong, J.M.; Currier, J.L.; Tothova, Z.; Manola, J.B.; Ganesan, S.; Lansdorp, P.M.; Collins, K.; Hahn, W.C. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proc. Natl. Acad. Sci. USA 2005, 102, 8222–8227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Mukherjee, S.; Firpo, E.J.; Wang, Y.; Roberts, J.M. Separation of telomerase functions by reverse genetics. Proc. Natl. Acad. Sci. USA 2011, 108, E1363–E1371. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Haendeler, J.; Drose, S.; Buchner, N.; Jakob, S.; Altschmied, J.; Goy, C.; Spyridopoulos, I.; Zeiher, A.M.; Brandt, U.; Dimmeler, S. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb. Vasc. Biol. 2009, 29, 929–935. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Mattiussi, M.; Tilman, G.; Lenglez, S.; Decottignies, A. Human telomerase represses ROS-dependent cellular responses to Tumor Necrosis Factor-alpha without affecting NF-kappaB activation. Cell Signal 2012, 24, 708–717. [Google Scholar] [CrossRef]
  148. Indran, I.R.; Hande, M.P.; Pervaiz, S. hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells. Cancer Res. 2011, 71, 266–276. [Google Scholar] [CrossRef] [Green Version]
  149. Singhapol, C.; Pal, D.; Czapiewski, R.; Porika, M.; Nelson, G.; Saretzki, G.C. Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis. PLoS ONE 2013, 8, e52989. [Google Scholar] [CrossRef]
  150. Zhou, J.; Mao, B.; Zhou, Q.; Ding, D.; Wang, M.; Guo, P.; Gao, Y.; Shay, J.W.; Yuan, Z.; Cong, Y.S. Endoplasmic reticulum stress activates telomerase. Aging Cell 2014, 13, 197–200. [Google Scholar] [CrossRef] [Green Version]
  151. Listerman, I.; Sun, J.; Gazzaniga, F.S.; Lukas, J.L.; Blackburn, E.H. The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis. Cancer Res. 2013, 73, 2817–2828. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Vuong, H.G.; Altibi, A.M.A.; Duong, U.N.P.; Hassell, L. Prognostic implication of BRAF and TERT promoter mutation combination in papillary thyroid carcinoma-A meta-analysis. Clin. Endocrinol. 2017, 87, 411–417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Therkildsen, C.; Bergmann, T.K.; Henrichsen-Schnack, T.; Ladelund, S.; Nilbert, M. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis. Acta Oncol. 2014, 53, 852–864. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Yuan, X.; Mu, N.; Wang, N.; Straat, K.; Sofiadis, A.; Guo, Y.; Stenman, A.; Li, K.; Cheng, G.; Zhang, L.; et al. GABPA inhibits invasion/metastasis in papillary thyroid carcinoma by regulating DICER1 expression. Oncogene 2019, 38, 965–979. [Google Scholar] [CrossRef]
  155. Zhang, S.; Zhang, K.; Ji, P.; Zheng, X.; Jin, J.; Feng, M.; Liu, P. GABPA predicts prognosis and inhibits metastasis of hepatocellular carcinoma. BMC Cancer 2017, 17, 380. [Google Scholar] [CrossRef] [Green Version]
  156. Guo, Y.; Yuan, X.; Li, K.; Dai, M.; Zhang, L.; Wu, Y.; Sun, C.; Chen, Y.; Cheng, G.; Liu, C.; et al. GABPA is a master regulator of luminal identity and restrains aggressive diseases in bladder cancer. Cell Death Differ. 2019. [Google Scholar] [CrossRef]
Cells 09 00749 g001 550
Figure 1. Mechanisms of telomerase reverse transcriptase (TERT) reactivation in cancer and TERT promoter (TERTp) mutations. (A) Different mechanisms of TERT reactivation in cancer according to Reference [10]. (B) Localization of TERTp mutations on Chromosome 5.
Figure 1. Mechanisms of telomerase reverse transcriptase (TERT) reactivation in cancer and TERT promoter (TERTp) mutations. (A) Different mechanisms of TERT reactivation in cancer according to Reference [10]. (B) Localization of TERTp mutations on Chromosome 5.
Cells 09 00749 g001
Cells 09 00749 g002 550
Figure 2. Distribution of TERT promoter mutations in different cancers.
Figure 2. Distribution of TERT promoter mutations in different cancers.
Cells 09 00749 g002
Table
Table 1. Prevalence and distribution of telomerase reverse transcriptase promoter (TERTp) mutations in cancer genomes. The prevalence of TERTp mutations is given as percentage and as total number of cases.
Table 1. Prevalence and distribution of telomerase reverse transcriptase promoter (TERTp) mutations in cancer genomes. The prevalence of TERTp mutations is given as percentage and as total number of cases.
Cancer TypeStagePrevalence of Mutations−146 C>T−124 C>TTert UpregulationMethodsSample OriginRemarksRef.
Central nervous system (CNS)
GBM 62%
24/39		25%
6/24		75%
18/24		YesDNA sequencing,
qRT-PCR, IHC,		Patients
(Portugal)		Associated with older age.[52]
GBMIV83.9%
47/55		34%
16/47		65.9%
31/47		YesDNA sequencing,
qRT-PCR, TRAP,
reporter assays		Patients
(China)		Associated with older age.[57]
GBM (Primary)IV83%
65/78		24.6%
16/65		75.4%
49/65		N/ADNA sequencingPatients
(US American)		Associated with shorter OS,
IDH-wt, ATRX-wt, exclusively in EGFRmut samples.		[77]
GBMI–IV44.6%
45/101		26.7%
12/45		73.3%
33/45		YesDNA sequencing,
qRT-PCR,
reporter assays		Patients
(China)		Associated with late-stage disease and patient age.
Only in gliomas, not in pituitary adenocarcinomas, meningiomas or secondary metastases.		[60]
GBM 55%
197/358		27%
54/197		73%
144/197		N/ADNA sequencingPatients
(Switzerland)		Associated with shorter OS and with EGFRmut.
Negatively associated with mutant IDH and TP53.
More frequent in primary (58%) than in secondary GBM (28%).
One patient with both −146 C>T + −124 C>T mutation.		[111]
GBM
(primary & secondary)		IV80.3%
143/178		**N/ADNA sequencingPatientsAssociated with shorter OS in patients without rs2853669 TERT
-245 A>G polymorphism.
Detected in 4/14 (28%) secondary GBM.		[81]
GBMIV66.9%
141/211		25.5%
36/141		74.5%
105/141		N/ADNA sequencingPatients (Portugal & Brazil)Associated with older age, poor prognosis, and shorter survival.
Reversed by rs2853669 TERT −245 A>G polymorphism.		[85]
GBM 60.4%
29/48		24.1%
7/29		75.8%
22/29		YesDNA sequencing,
qRT-PCR		Patients (Korea)Associated with older age.
Not associated with OS or DFS.
Associated with MGMT methylation and EGFR amplification.
Associated with rs2853669 TERT −245 A>G polymorphism (21/29 patients).
rs2853669 TERT −245 A>G polymorphism reversed TERT upregulation by TERTp mutations.		[64]
GBM 73%
92/126		28%
26/92		82%
66/92		YesDNA sequencing,
qRT-PCR, TRAP,
qPCR		 Mutually exclusive with IDH-1 mutations.
Associated with shorter telomeres.
Associated with lower OS in IDH-1wt patients.
rs2853669 TERT -245 A>G polymorphism associated with improved OS in patients without TERTp mutations, and with worse OS in patients with TERTp mutations.		[65]
GBM (primary) 86%
79/92		25%
20/79		75%
69/79		 DNA sequencing Associated with older age and shorter OS.
Homozygous rs2853669 TERT −245 A>G polymorphism associated with worse OS in patients without and with TERTp mutations.		[84]
GBM and gliomas (primary) 100%
10/10		10%
1/10		90%
9/10		N/ADNA sequencingPatientsIn primary GBM, characterized by 10q deletion EFGR amplification.[58]
GBM 94%
33/35		36%
12/33		64%
21/33		2.2–286-fold compared to normal astrocytesDNA sequencing,
qRT-PCR		Cell lines [58]
Total GBM 905/1331
(68%)		206/762
(27%)		567/762
(73%)
OligodendrogliomaII45%
10/22		20%
2/10		80%
8/10		YesDNA sequencing,
qRT-PCR, IHC		Patients
(Portugal)		 [52]
OligodendrogliomaII–III70%
7/10		14.3%
1/7		85.7%
6/7		YesDNA sequencing,
qRT-PCR, TRAP,
Reporter Assays		Patients
(China)		Associated with older age.[57]
OligodendrogliomaII–III46.3%
25/54		24%
6/25		76%
19/25		N/ADNA sequencingPatients
(Portugal &
Brazil)		Associated with older age at diagnosis.
Not associated with lower survival.		[85]
Oligodendroglioma 73.5%
25/34		20%
5/25		80%
20/25 		YesDNA sequencing,
qRT-PCR		Patients
(Japan)		Associated with total 1p19q loss and IDH-1/2 mutations (98%) but
exclusive with IDH-1mut if not total loss of 1p19q.		[53]
OligodendrogliomaII–IV66.81%
151/226		**N/ADNA sequencingPatients
(US American)		Associated with shorter OS.
Can be associated with ATRX mutations or IDHmut/1p19q loss.		[80]
OligodendrogliomaII–III63.2%
12/19		41.7%
5/12		58.3%
7/12		N/ADNA sequencingPatients
(US American)		IDH-wt only.
Associated with worse prognosis in IDH-wt.
Associated with older age.
Mutually exclusive with ATRX mutations.		[77]
Anaplastic
oligodendroglioma		III54%
13/24		30.8%
4/13		69.2%
9/13		YesDNA sequencing,
qRT-PCR, IHC,		Patients
(Portugal)		Associated with older age.[52]
Anaplastic
oligodendroglioma		 74.2%
23/31		30.4%
7/23		69.6%
16/23 		YesDNA sequencing,
qRT-PCR		Patients
(Japan)		Associated with total 1p19q loss and IDH-1/2 mutations (98%) but
exclusive with IDH-1 if not total loss of 1p19q.		[53]
Anaplastic
oligodendroglioma		III88.5%
23/26		43.5%
10/23		56.5%
13/23		N/ADNA sequencingPatients
(US American)		Associated with older age.
IDH-wt only.
Associated with worse prognosis in IDH-wt.
Mutually exclusive with ATRX mutations.		[77]
Total
Oligodendroglioma		 289/446
(64.7%)		40/138
(29%)		98/138
(71%)
Diffuse astrocytomas 19.2%
10/52		20%
2/10		80%
8/10		YesDNA sequencing,
qRT-PCR		Patients
(Japan)		Associated with total 1p19q loss and IDH-1/2 mutations (98%) but
exclusive with IDH-1 if not total loss of 1p19q.		[53]
Diffuse astrocytomaII15%
3/20		33,3%
1/3		66,6%
2/3		YesDNA sequencing,
qRT-PCR, IHC		Patients
(Portugal)		Associated with older age.[52]
Diffuse astrocytomaII20%
8/40		25%
2/8		62.5%
5/8		YesDNA sequencing,
qRT-PCR, TRAP,
reporter assays		Patients
(China)		Associated with age.[57]
Diffuse astrocytomaII15.2%
7/46		16.7%
1/7		83.3%
6/7		N/ADNA sequencingPatients
(Portugal &
Brazil)		Frequency increased with grade.[85]
Total Diffuse Astrocytoma 28/158
(17.7%)		6/28
(21.4%)		21/28
(75%)
AstocytomaII–IV62.5%
416/665		N/AN/AN/ADNA sequencingPatients
(US American)		Associated with shorter OS.
Can be associated with ATRX mutations or IDHmut/1p1q loss.		[80]
Anaplastic AstrocytomasIII10%
1/10		0%
0/1		100%
1/1		N/ADNA sequencingPatients
(Portugal &
Brazil)		Frequency increased with grade.[85]
Anaplastic AstrocytomaIII33.3%
4/12		0%
0/4		100%
4/4		YesDNA sequencing,
qRT-PCR, TRAP,
reporter assays		Patients
(China)		Correlation with age.[57]
Anaplastic AstrocytomasIII25.3%
20/79		20%
4/20		80%
16/20		YesDNA sequencing,
qRT-PCR		Patients
(Japan)		Associated with total 1p19q loss and IDH-1/2 mutations (98%) but exclusive with IDH-1 if not total loss of 1p19q.[53]
Total Anaplastic Astrocytomas 25/101
(24.7%)		4/25
(16%)		21/25
(84%)
Mixed OligoastocytomaII–IV32.3%
63/195		**N/ADNA sequencingPatients
(US
American)		Associated with shorter OS.
Can be associated with ATRX mutations or IDHmut/1p1q loss.		[80]
Oligoastrocytoma 40%
14/35		28.6%
4/14		71.4%
10/14		YesDNA sequencing,
qRT-PCR		Patients
(Japan)		Associated with total 1p19q loss and IDH-1/2 mutations (98%) but exclusive with IDH-1 if not total loss of 1p19q.[53]
OligoastrocytomaII–III40.0%
4/10		50%
2/4		50%
2/4		N/ADNA sequencingPatients
(Portugal & Brazil)		Not associated with lower survival.[85]
Anaplastic Oligoastrocytoma 48.9%
22/45		27.3%
6/22		72.7%
16/22		YesDNA sequencing,
qRT-PCR		Patients (Japan)Associated with total 1p19q loss and IDH-1/2 mutations (98%) but exclusive with IDH-1 if not total loss of 1p19q.[53]
Total
Oligoastrocytoma		 103/285
(36.1%)		12/40
(30%)		28/40
(70%)
Medulloblastoma 33.3%
2/6		50%
1/2		50%
1/2		N/ADNA sequencingPatients (China)Associated with age.[57]
Medulloblastoma 20.9%
19/91		0%0/19100%
19/19		N/ADNA sequencingPatients
(US American)		IDH-wt and ATRX-wt only.
Associated with worse prognosis in IDH-1-wt.
Associated with older age.
Mutually exclusive with ALT.		[77]
Total
Medulloblastoma		 21/97
(21.6%)		1/21
(4.7%)		20/21
(95.3%)
Skin
Melanoma 71%
50/70		46%
23/50		54%
27/50		YesDNA sequencing,
reporter vectors		Patients
& cell lines		 [50]
Melanoma 32.5%
25/77		20%
5/25		28%
7/25		N/ADNA sequencingPatients-57 C>T germline mutation in family with history of melanoma.
High prevalence in metastatic cell lines (85%) compared to primary melanoma (32.5%).
CC>TT −139/−138 tandem mutation in 10.4% patients.
Concomitant with BRAF mutations in 47% of cases.		[49]
Melanoma 29%
16/56		50%
8/16		50%
8/16		N/ADNA sequencingPatients
(Portugal)		Associated with BRAF mutations.[52]
Melanoma 34%
97/287		52.5%
51/97		36%
35/97		YesDNA sequencing,
qRT-PCR		Patients
(Spain)		CC>TT −139/−138 tandem mutations in 4/97 (4.1%) patients.
Associated with BRAF mutations in 50% cases.		[88]
Melanoma 41.6%
121/291		**N/ADNA sequencingPatients (Spain)Associated with shorter telomeres in tumor and with accelerated telomere shortening rate.
Associated with BRAF/NRAS mutation in 75/243 cases.
Telomere shortening rate: BRAF/NRASmut+TERTpmut>TERTpmut>BRAF/NRASmut		[115]
Melanoma 22%
26/116		35%
9/26		46%
12/26		YesDNA sequencing,
IHC		Patients
(Portugal)		Associated with reduced OS & DFS.
More prevalent in sun-exposed regions.
Associated with increased mitotic rates.
−138/−138 CC>TT tandem mutation in 2/26 (7.7%) patients.
−125/−124 CC>TT tandem mutation in 3/26 (11.5%) patients.
Associated with BRAF-V600E mutation (58% of cases).		[89]
Melanoma 38.6%
116/300		50%
58/116		32.8%
32/116		N/ADNA sequencingPatients (Spain)Associated with shorter OS and DFS.
−139/−138 CC>TT & −125/−124 CC>TT tandem mutations in 16/116 cases (13.8%).
Associated with BRAF/NRAS mutations in 126/283 (44.5%) cases.
Reversed by rs2853669 TERT -245 A>G polymorphism.		[116]
Melanoma 54.8%
63/115		61.9%
39/63		30.2%
19/63		N/ADNA sequencingPatients (Austria)−139/−138 CC>TT tandem mutations in 4/63 (6.3%) patients.
−125/−124 CC>TT tandem mutation in 1/63 (1.6%) patient.
Associated with BRAF/NRAS mutation in 75/243 cases.
Associated with rs2853669 TERT -245 A>G polymorphism.		[91]
Total Melanoma 514/1312
(39.2%)		193/398
(48.5%)		140/398
(35.1%)
Basal cell carcinoma 55.6%
18/32		55.6%
10/18		22.2%
4/18		N/ADNA sequencingPatients (Germany) [55]
Basal cell carcinoma
(sporadic & nevoid)		 74%
31/42		35.5%
11/31		45.1%
14/31		N/ADNA sequencingPatientsMostly homozygous.
−139/−138 CC>TT tandem mutation in 7/31 (22.6%) patients.
−125/−124 CC–TT tandem mutation in 5/31 (16.1%) patients.
1 patient with −139/−138 CC>TT + −125/−124 CC>TT tandem mutations.
Mutations more frequent in basal cell carcinoma than in squamous cell carcinoma.		[90]
Basal cell carcinoma 38.7%
76/196		43%
33/76		49%
37/76		noDNA sequencing,
IHC		Patients
(Portugal)		No correlation with clinical parameters.
Higher prevalence in patients not exposed to X-irradiation: 48/94 (51%) vs. 28/102 (27%) in X-irradiated patients.
−124 C>T more frequent than −146 C>T in non-X-irradiated patients;
−146 C>T more frequent in X-irradiated patients.
−139/138 CC>TT tandem mutation in 2/76 (2.6%) patients,
2 patients with −146 C>T + −124 C>T mutations.		[89]
Total Basal cell carcinoma 125/270
(46.2%)		54/125
(43.2%)		55/125
(44%)
Cutaneous SCC 50%
17/34		29.4%
5/17		29.4%
5/17		N/ADNA sequencingPatients (Germany) [55]
Cutaneous SCC 50%
13/26		54%
7/13		31%
4/13		N/ADNA sequencingPatientsMostly homozygous.
−139/−138 CC>TT tandem mutation in 2/13 (15.4) patients.
Mutations more frequent in basal cell carcinoma than in squamous cell carcinoma.		[90]
Total Cutaneous SCC 30/60
(50%)		12/30
(40%)		9/30
(30%)
Bladder/urinary tract cancers
Bladder Cancer 85%
44/52		4.5%
2/44		95.5%
42/44		N/ADNA sequencingPatients (China) [78]
Urothelial bladder carcinomaIII80%
12/15		17%
2/12		83%
10/12		N/ADNA sequencingPatients
(US American)		 [93]
Urothelial bladder carcinoma 66.7%
14/21		28.6%
4/14		71.4%
10/14		N/ADNA sequencingPatients
(US American)		 [77]
Urothelial bladder carcinoma 61.7%
148/240		25%
37/148		58.8%
87/148		N/ADNA sequencingPatients (China)Not associated with age.[57]
Urothelial bladder carcinoma 59%
48/82		37.5%
18/48		62.5%
30/48		N/ADNA sequencing, qRT-PCR Patients (Portugal)Not associated with age.
Low-grade bladder cancer: 67%,
high-grade bladder cancer: 56%.		[52]
Urothelial bladder carcinoma 65.4%
214/327		17.8%
38/214		81.8%
175/214		N/ADNA sequencing, relative telomere lengthPatients (Sweden)Associated with shorter telomeres and worse OS.
Associated with FGFR3 mutation in 45% of tumors.
FGFR3 mutations found in low-grade tumors, TERTp mutations in low-grade and high-grade tumors.
Reversed by rs2853669 TERT −245 A>G polymorphism.		[61]
Urothelial bladder carcinoma 77.1%
361/468		17%
62/361		83%
299/361		Not increasedDNA sequencing, qRT-PCRPatientsNot associated with OS, DFS, or clinical outcome.
Associated with FGFR3mut.		[94]
Urothelial bladder carcinoma 100%
33/33		12%
5/33		85%
28/33		N/ADNA sequencingPatientsPure micropapillary carcinoma and urothelial cancer with focal micropapillary features.[92]
Urothelial upper tract urinary carcinoma 76.9%
40/52		12.5%
5/40		72.5%
29/40		N/ADNA sequencingPatients
(China)		Not associated with age.[57]
Urothelial upper tract urinary carcinoma 47.4%
9/19		11.1%
1/9		88.9%
8/9		N/ADNA sequencingPatients
(US American)		 [77]
Urothelial upper tract urinary carcinoma 29.5%
65/220		18.5%
12/65		81.5%
53/65		N/ADNA sequencing,
Detection in urine		Patients (China)Associated with distant metastases.[118]
Total Urothelial bladder & upper tract urinary carcinoma 988/1529
(64.6%)		186/988
(18.8%)		771/988
(78%)
Thyroid
Differentiated thyroid cancer 12.2%
41/336		4.9%
2/41		95.1%
39/41		N/ADNA sequencingPatientsOnly in malignant lesions.[108]
Papillary thyroid cancer 8%
13/169		7.7%
1/13		84.6%
11/13		YesDNA sequencing,
qRT-PCR, IHC		Patients
(Portugal)		 [52]
Papillary thyroid cancerIII/IV11.3%
46/408		15.2%
7/46		85.8%
39/46		N/ADNA sequencingPatients (China)Associated with older age, larger tumor size, extrathyroid invasion, advanced clinical stage.
Associated with BRAF-V600E mutation.		[99]
Papillary thyroid cancer 27%
13/51		7.7%
1/13		92.3%
12/13		N/ADNA sequencingPatients (Sweden)Only in patients >45.
Correlated with shorter telomeres and distal metastases.
PTC: 27% (25/332); FTC: 22% (12/70); ATC: 50% (12/36).		[98]
Papillary thyroid cancerIII/IV4.1%
18/432		**N/ADNA sequencingPatients (Korea)Associated with BRAF/RAS mutations.
Associated with tumor size, stage III-IV, recurrence, decreased OS and DFS with BRAF/RAS mutations: RAS/BRAF >TERTp > RAS/BRAF+TERTp.		[106]
Papillary thyroid cancer 11.7%
30/257		0%
0/30		100%
30/30		N/ADNA sequencingPatientsOnly in malignant lesions.
−124 C>T associated with BRAF-V600E mutation.		[108]
Papillary thyroid cancer 37.7%
10/27		10%
1/10		90%
9/10		N/ADNA sequencingPatients (Korea)No TERTp mutation found in 192 well differentiated cancers without distant metastasis.[105]
Papillary thyroid cancer 22%
18/80		44%
8/18		66%
10/18		N/ADNA sequencingPatients
(US & Japan)		More frequent in BRAF-wt patients than in BRAFmut.[100]
Papillary thyroid cancer 31.8%
77/242		0%
0/77		100%
77/77		N/ADNA sequencingPatients
(US)		Associated with older age (>45 years), larger tumor size, stage III–IV, distant metastases, decreased OS and DFS.
rs2853669 TERT −245 A>G polymorphism (46.7% (113/242)of patients) increases OS & DFS in patients without TERTp mutations and with BRAF-V600E.		[103]
Papillary thyroid cancer 12%
22/182		14.6%
3/22		86.4%
19/22		YesDNA sequencing,
WB, and IHC		Patients
(Italy)		Associated with older age and poor prognosis.
Increased cytoplasmic localization of TERT.
No impact of rs2853669 TERT -245 A>G polymorphism on outcome.		[102]
Total Papillary thyroid cancer 247/1848
(13.4%)		21/229
(9.2%)		207/229
(90.4%)
Follicular Thyroid Cancer 13.9%
11/79		18.2%
2/11		81.8%
9/11		N/ADNA sequencingPatientsOnly in malignant lesions. [108]
Follicular Thyroid Cancer 66.7%
2/3		50%
1/2		50%
1/2		N/ADNA sequencingPatients (Korea)No TERTp mutation found in 192 well-differentiated cancers without distanst metastasis.[105]
Follicular thyroid Cancer 14%
9/64		22.2%
2/9		77.8%
7/9		YesDNA sequencing,
qRT-PCR, IHC		Patients (Portugal) [52]
Follicular thyroid cancer 22%
8/36		12.5%
1/8		87.5%
7/8		N/ADNA sequencingPatients (Sweden)Increased prevalence in ATC: PTC: 27% (25/332); FTC: 22% (12/70); ATC: 50% (12/36).[98]
Follicular thyroid cancer 36.4%
8/22		12.5%
1/8		87.5%
7/8		N/ADNA sequencingPatients (China)Associated with older age, larger tumor size, extrathyroid invasion, advanced clinical stage.
Associated with BRAF-V600E mutation.		[99]
Follicular thyroid cancerIII/IV5.9%
7/119		**N/ADNA sequencingPatients (Korea)Associated with BRAF/RAS mutations.
Associated with tumor size, stage III-IV, recurrence, decreased OS and DFS with BRAF/RAS mutations: RAS/BRAF >TERTp > RAS/BRAF+TERTp.		[106]
Follicular thyroid cancer 14%
8/58		38.5%
3/8		62.5%
5/8		YesDNA sequencing,
WB, and IHC		Patients (Italy)Associated with older age and poor prognosis.
Increased cytoplasmic TERT.
No impact of rs2853669 TERT -245 A>G polymorphism on outcome. 		[102]
Total Follicular thyroid cancer 53/381
(13.9%)		10/46
(21.7%)		36/46
(78.2%)
Poorly differentiated thyroid cancer 21%
3/14		33.3
1/3		66.7
2/3		YesDNA sequencing,
qRT-PCR, IHC		Patients (Portugal) [52]
Poorly differentiated thyroid cancer 37.5%
3/8		0%
0/3		100%
3/3		N/ADNA sequencingPatientsOnly in malignant lesions. [108]
Poorly differentiated thyroid cancer 29%
2/7		50%
1/2		50%
1/2		N/ADNA sequencingPatients (Korea)No TERTp mutation found in 192 well-differentiated cancers without distanst metastasis.[105]
Poorly differentiated thyroid cancer 51.7%
30/58		40%
12/30		60%
18/30		N/ADNA sequencingPatients
(US & Japan)		More prevalent in advanced cancer patients with BRAF/RASmut.[100]
Total Poorly differentiated thyroid cancer 38/87
(43.7%)		14/38
(36.8%)		24/38
(63.2%)
Anaplastic thyroid cancer 46.3%
25/54		8%
2/25		92%
23/25		N/ADNA sequencingPatientsOnly in malignant lesions.[108]
Anaplastic thyroid cancer 13%
2/16		50%
1/2		50%
1/2		YesDNA sequencing, qRT-PCRPatients (Portugal) [52]
Anaplastic thyroid cancer 50%
10/20		0%
0/10		100%
10/10		N/ADNA sequencingPatients
(US & Japan)		More prevalent in advanced cancer patients with BRAF/RASmut.[100]
Anaplastic thyroid cancer 50%
10/20		20%
2/10		80%
8/10		N/ADNA sequencingPatients (Sweden)PTC: 27% (25/332); FTC: 22% (12/70); ATC: 50% (12/36).[98]
Anaplastic thyorid cancer 33.3%
12/36		**N/ADNA sequencingPatients
(Portugal & Spain)		Associated with older age, larger tumor size, distant metastases and disease-related death in FTC.
PTC: 7.5% (25/332); FTC: 17.1% (12/70); PDTC: 29% (9/31); ATC: 33.4% (12/36).
PTC associated with BRAF-V600E mutation in 60.3% of cases.		[101]
Anaplastic thyroid cancer 38.7%
41/106		10%
4/41		90%
37/41		N/ADNA sequencingPatients
(US & China)		Associated with older age and distal metastases.
−124 C>T found in 56.3% of BRAF-V600E mutated cases.		[104]
Total anaplastic thyroid cancer 100/252
(39.7%)		9/88
(10.2%)		79/88
(89.7%)
Thyroid Cancer cell lines 91.7%
11/12		27.3%
3/11		72.7%
8/11		N/ADNA sequencingCell lines [108]
Thyroid Cancer cell lines 75%
6/8		17.7%
1/6		83.3%
5/6		N/ADNA sequencingATC cell lines [98]
Liver-Hepatocellular Carcinoma (HCC)
HCC 31.4%
11/35		18,2%
2/11		81,8%
9/11		N/ADNA sequencingPatients (China) [57]
HCC 34%
15/44		33.3%
5/15		66.7%
10/15		N/ADNA sequencingPatients
(Africa, Asia, Europe)		Higher TERTp mutation prevalence in African (53%) compared to non-African (24%) populations.[97]
HCC 44.3%
27/61		3.7%
1/27		96.3%
26/27		N/ADNA sequencingPatients
(US American)		Detected in both HBV-associated and HBV-independent HCC
Frequent in HCV-associated HCC.		[77]
HCC 48.5%
65/131		3.1%
2/65		96.9%
63/65		N/ADNA sequencingPatients (Italy)41% of mutations in HBV-associated HCC.
53.6% mutations in HCV-associated HCC.
All heterozygous.
No −57 A>C.		[95]
HCC 31%
85/275		1.1%
1/85		98.9%
84/85		YesDNA sequencing, IHCPatients (China)HBV-associated HCC.
Correlated with age, not with HBV status.
Found in 4/7 preneoplastic lesions (HBV-associated HCC).		[63]
HCC 65.4%
68/104		3%
2/68		97%
66/68		YesDNA sequencingPatients (Japan)Associated with older age.
Associated with shorter OS and DFS.
Associated with HCV infection and excluded from HBV+ HCC.		[122]
HCC 58.6%
179/305		6.1%
11/179		92.7%
166/179		Yes
2–10-fold 		DNA sequencing, qRT-PCRPatients (French)Detected in cirrhotic preneoplastic macronodules (25%) and cirrhotic adenomas (44%), at last step of malignant transformation into HCC.
Absent from HBV-associated tumors 2/179 (1%) −146 C>T.		[62]
HCC 29.3%
57/195		5.3%
3/57		94.7%
54/57		NoDNA sequencing, qRT-PCR Associated with older age.
No impact on overall survival.
Excluded from HBV-associated HCC.
Higher frequency in HCV-associated HCC.		[96]
HCC 54%
254/469		4.3%
11/254		93%
236/254		N/ADNA sequencingPatients (Japan, US-European ancestry)−57 A>C mutation detected in 1.6%.
Present in 37% HBV-associated HCC but mutually exclusive with HBV sequence integration.
Mutually exclusive with TERT CNV and ATRX mutations.
Associated with HCV infection (64% or TERTp mutations).
Associated with Wnt pathway mutations.		[121]
HCC 60%
9/15		11.1%
1/9		88.9%
8/9		N/ADNA sequencingCell lines [97]
Total HCC 770/1634
(47.1%)		39/770
(5%)		722/770
(93.7%)
Cervical
Cervical SCC 21.8%
22/101		31.8%
7/22		45.5%
10/22		YesqRT-PCRPatients (Italian women) [37]
Cervical SCC 21.4%
30/140		26.7%
8/30		73.3%
22/30		N/ADNA sequencing, Association with clinical statusPatients (Indian women)75% TERTp mutations in HPV-negative samples.
−124 C>T 6/22 were TT homozygous.
−146 C>T 2/8 were TT homozygous.		[36]
Cervical SCC 4.5%
1/22		100%
1/1		0%
0/1		N/ADNA sequencingPatients
(US American)		1 patient with −125 C>A mutation.
Total Cervical SCC 53/263
(20.1%)		16/53
(30.2%)		32/53
(60.4%)		 [77]
Head and Neck Squamous Cell Carcinoma (HNSCC)
HNSCC 31.7%
13/41		30.8%
4/13		69.2%
9/13		N/ADNA sequencingPatients (Indian women)Association with clinical status.[36]
HNSCC 17%
12/70		16.7%
2/12		83.3%
10/12		N/ADNA sequencingPatients
(US American)		11/12 HNSCC with TERTp mutations were in the oral tongue, and 11/23 (47.8%) of HNSCC of the oral tongue harbored TERTp mutations.[77]
Total HNSCC 25/111
(22.5%)		6/25
(24%)		19/25
(76%)
Ovarian cancer
Ovarian clear cell carcinoma 15%
3/20		0%
0/3		10%
2/3		N/ADNA sequencingPatients
(US American)		1 patient with −124 C>A mutation.[77]
Ovarian clear cell carcinoma 16.5%
37/233		8.1%
3/37 		91.9%
34/37		N/ADNA sequencing,
IHC, telomere length evaluation		PatientsNo link with survival or age.
TERTp mutations tended to be mutually exclusive with loss of ARID1A protein expression and PIK3CA mutation.		[132]
Ovarian clear cell carcinoma 30%
3/10		0%
0/3		100%
3/3		YesqRT-PCRCell lines [132]
Total ovarian clear cell carcinoma 43/263
(16.3%)		3/43
(6.9%)		39/43
(90.7%)
N/A: not assessed; *: data not available. TERT: telomerase reverse transcriptase; GBM: glioblastoma multiforme; SCC: squamous cell carcinoma; HNSCC: head and neck squamous cell carcinoma; HCC: hepatocellular carcinoma; GI: gastrointestinal; UC: urothelial cancer; MPC: micropapillary carcinoma; HPV: Human papilloma virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; PTC: papillary thyroid cancer; FTC: follicular thyroid cancer; ATC: anaplastic thyroid cancer.

Share and Cite

MDPI and ACS Style

Hafezi, F.; Perez Bercoff, D. The Solo Play of TERT Promoter Mutations. Cells 2020, 9, 749. https://doi.org/10.3390/cells9030749

AMA Style

Hafezi F, Perez Bercoff D. The Solo Play of TERT Promoter Mutations. Cells. 2020; 9(3):749. https://doi.org/10.3390/cells9030749

Chicago/Turabian Style

Hafezi, François, and Danielle Perez Bercoff. 2020. "The Solo Play of TERT Promoter Mutations" Cells 9, no. 3: 749. https://doi.org/10.3390/cells9030749

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop