Human telomerase reverse transcriptase and telomeres in cancer

Anurag Mehta; Shrinidhi Nathany

doi:10.4103/jco.jco_26_21

EDITORIAL

Year : 2021 | Volume : 4 | Issue : 1 | Page : 1-4

Human telomerase reverse transcriptase and telomeres in cancer

Anurag Mehta¹, Shrinidhi Nathany²
¹ Department of Research and Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
² Molecular Diagnostics Laboratory, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India

Date of Submission	05-Jul-2021
Date of Acceptance	06-Jul-2021
Date of Web Publication	31-Jul-2021

Correspondence Address:
Dr. Anurag Mehta
Director of Laboratory Services and Molecular Diagnostics, Department of Research and Pathology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Sector-5, New Delhi.
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jco.jco_26_21

How to cite this article:
Mehta A, Nathany S. Human telomerase reverse transcriptase and telomeres in cancer. J Curr Oncol 2021;4:1-4

How to cite this URL:
Mehta A, Nathany S. Human telomerase reverse transcriptase and telomeres in cancer. J Curr Oncol [serial online] 2021 [cited 2023 Nov 30];4:1-4. Available from: http://www.https://journalofcurrentoncology.org//text.asp?2021/4/1/1/322893

Introduction

Telomeres are 4–10 kb long, hexameric repeats of TTAGGG found at the ends of chromosomes followed by a G-rich 3′-overhang.^[1] The overhang accords stability to the telomere by forming protective T and D loops [Figure 1]. In addition, a complex of a multiunit protein called Shelterin stabilizes the telomeres.^[2] The telomeres protect the ends of the chromosomes by forming a cap that works like an aiglet of a drawstring, foiling loss of chromosomal DNA from the ends and any undesirable DNA recombination between raw ends.^[3] By ensuring the latter, the telomeres help retain genomic fidelity during replication. However, every replicative cycle draws a toll on telomere length, shortening them by 25–200 bases. The “end of replication problem” of replacing the RNA primer sequence in the lagging strand and the oxidative stress are two important reasons for this loss.^[1] Once the telomeres reach a critical length, the DNA damage response is initiated causing cell death by apoptosis. This phenomenon imposes a replicative limit of 50–70 divisions and is referred to as the Hayflick limit. Although this may seem an unfavorable event, it is beneficial in that it helps eliminate genetically altered, biologically exhausted or damaged cells. Cellular senescence is therefore a crucial anticancer mechanism averting the growth of cells disposed to neoplastic transformation. In addition, telomeres function as regulatory elements affecting transcriptional repression of genes close to the telomeres called telomere position effect (TPE) and even those located at long distances designated as TPE over long distances (TPE-OLD).^[4]

Figure 1: Structure of a telomere. The Shelterin protein complex provides for recognition of TTAGGG telomeric repeats and complex stabilizing proteins. The T loop hides the DNA ends, preventing recombination

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Although senescence is protective in somatic cells, it will be an intolerable event in germ cells, embryonic cells, progenitor cells, and stem cells. These cells maintain a constant telomere length by a reverse transcriptase (hTERT—human telomerase reverse transcriptase) that harbors within it an 11-nucleotide long sequence acting as a template for synthesis of telomeric repeats (hTERC—human telomerase RNA component) [Figure 2].^[5] The hTERT uses the complementary sequence within it to elongate the size of the telomere and restore the telomere to their normal size in the aforementioned cells [Figure 3]. However, this activity is minimal in somatic cells and as said before is a safety mechanism to delete aged cells with genomic instability.

Figure 2: Illustration of hTERT within which reside 11 nucleotides complementary to repeat sequences of telomere called telomerase RNA component (hTERC)

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Figure 3: Step 1: The shortened telomere after replication. Step 2: TERT recognizes the shortened telomere and adds complementary nucleotides using TERC. Step 3: The process is repeated many times till the length is restored to almost the original size. The lagging strand is also elongated using polymerase α and primase. The end repair problem, however, prevents flush ends at termini and creates a 3′-overhang

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Telomere and Cancer

Cancer cells appropriate high telomerase activity resulting in indefinite survival and unlimited replicative ability.^[6] The TERT transcript and enzyme overexpression are seen in 85% of cancer, indicating that telomerase is principally regulated by TERT gene expression.^[7] How is the TERT activity upregulated in a cancer cell which is a transformed somatic cell that had partially exhausted its TERT? The mechanisms of TERT activation include the following [Figure 4].^[8]
Figure 4: Illustrative summary of the role of canonical and non-canonical activation of hTERT and its role in oncogenesis

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- A. Gain-of-function mutations in the TERT promoter sequence: The TERT promoter mutations have been identified at two hotspots −124 (C228T), −146 (C250T) and rarely at a few other sites.^[2] These mutations generate 5′-CCCCTTCCGGGG-3′, which is the binding site for the E-26 family of transcription factors (ETS) upregulating transcription and overexpression. TERT promoter mutations have been commonly reported in melanoma, especially cutaneous melanoma, glioblastoma, urothelial carcinoma, and to a lesser extent in hepatocellular (HCC), adrenocortical, and thyroid carcinomas. Rarely, these may be detected in kidney, lung, prostate, and gastrointestinal (GI) cancer in frequencies of less than 10%. These mutations are associated with aggressive phenotypes, metastasis, and adverse outcomes.^[8],[9],[10]
- B. Co-occurrence of TERT promoter mutations and BRAF/KRAS mutations: BRAF/KRAS mutations have been observed beyond chance relationship to co-occur with TERT promotion mutations. The activation of the MAPK pathways by gain-of-function mutations in BRAF/KRAS upregulates ETS transcriptional factors that, in turn, increase TERT expression.^[11] This positive association has been reported by Vallarelli et al.^[12] in melanoma and Liuet al.^[13] in non-small cell lung carcinoma.
- C. Amplification of TERT gene: TERT is amplified in approximately 4% of cancers, especially well-differentiated/de-differentiated liposarcoma, endometrial cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma, esophageal carcinoma, and adrenocortical carcinoma.^[9],[14]
- D. TERT rearrangement: TERT rearrangement as a cause of TERT induction and immortalization in human fibroblasts were described by Zhao et al.^[15] Recently, using high-throughput sequencing, this alteration has been identified to activate telomerase in several cancers, especially neuroblastoma, and also in glioblastoma, meningiomas, malignant melanoma, pheochromocytomas besides several others.
- E. TERT isoforms: More than 20 TERT isoforms have been identified and produced by alternate splicing of pre-mRNA. Although only the full-length isoform has reverse transcriptase activity and the capability to maintain the telomere length, the other isoforms confer growth advantage and stemness. A variant with exon 4–13 skipping (Δ4–13) has specially been shown to cause higher proliferation rates by activating the WNT-β-catenin pathway. Another study described a beta-deletion isoform that accords growth advantage to breast cancer cells, independent of telomere maintenance.^[16],[17]
- F. Hypermethylation of CpG islands in TERT promoter sequence: TERT-hypermethylated oncological region (THOR) is a 433-bp-long region upstream of the TERT core promoter that harbors 52 CpG sites. Unmethylated THOR binds transcription repressor factors and represses TERT. Cancer-specific methylation in THOR abolishes the repressor binding sites, upregulating TERT. In addition, it allows the recruitment of enhancers to TERT core promoter further augmenting TERT transcription and translation.^[9],[18]

Interaction of other signaling pathways with TERT: In addition to the aforementioned mechanisms of TERT activation heedless of contributions from other pathways, it has recently been observed that many signaling pathways, particularly c-MYC, NF-κB, and WNT-beta-catenin, aid in the transcriptional activation of TERT in cancers. TERT activation is initiated by c-MYC that binds to enhancer box 5′-CACGTG-3′ in the TERT promoter. NF-κB controls the transcription of TERT via NF-κB binding sites in the TERT promoter. Wnt/B-catenin is another pathway involved in the regulation of TERT. Activation of this pathway confers stemness, cellular replication, and cancer progression.^{[1],[2],[10],[11]}

The Clinical Applications

The applications of finding these mutations are many. The presence of TERT promoter mutations in urine samples has been used as a marker of residual or recurrent bladder cancer. The detection of TERT promoter mutations by use of liquid biopsy has been used for the diagnosis/monitoring of HCC, bladder cancer, and glioblastoma. Tracking of TERT promoter mutations using digital droplet PCR has been used to monitor response to therapy in cutaneous melanoma.^[19] Another significant use of these mutations is in the separation of primary glioblastoma from secondary glioblastoma with the former carrying these mutations in 70% of the cases, against the lack of it in the latter. Also, TERT mutations occurred predominantly in IDH1, wild high-grade gliomas, providing an additional layer of diagnostic confirmation. Liu et al^[20] identified TERT promoter methylation in two cases of gastrointestinal cancers and it has been shown that methylated promoter sites in TERT from the stool of gastrointestinal cancer patients, with sensitivity and specificity is comparable to a fecal occult blood test. The presence of TERT mutations in papillary thyroid carcinoma, glioblastoma, and bladder cancer has been linked with inferior outcomes. In addition, TERT promoter hypermethylation has been linked to progression and poor survival outcomes in brain tumors and adrenocortical carcinoma.

Conclusion

TERT gene alterations reactivate the repressed TERT in somatic cells conferring oncogenic potentials. It has been identified as an early and common event in carcinogenesis. TERT alterations and TERT overexpression have been positively correlated with an aggressive phenotype, metastasis, and inferior outcomes. Potential clinical applications are many, although these are seldom used in clinical decision making outside CNS tumors. Future research and a better understanding of TERT interaction with other signaling pathways and understanding of its mechanistic nuances in carcinogenesis beyond maintaining telomere length can provide a route to its therapeutic engagement.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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