Occurrence, functionality and abundance of the TERT promoter mutations

Abstract

Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through the reactivation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene represent a definite mechanism for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate increase in TERT transcription and consequent telomerase upregulation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies have resolved the discrete aspects, effects and clinical relevance of the TERT promoter mutations. The promoter mutations link transcription of TERT with oncogenic pathways, associate with markers of poor outcome and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism of TERT activation. We further deliberate on the foundational question of the abundance of the TERT promoter mutations and a general dearth of functional mutations within noncoding sequences, as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within the TERT promoter may be less than a common occurrence in other noncoding functional elements. Besides, the evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.

Mutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development

“…The role of TERTp mutations in the development of melanoma has been widely studied since the stabilization of telomeres in cells is one of the hallmarks of cancer [41,42]. In our study, CSD melanomas showed a higher prevalence of mutations within the promoter region of TERT, albeit without statistical significance.…”

A Qualitative Signature to Identify TERT Promoter Mutant High-Risk Tumors in Low-Grade Gliomas

“…In IDH wildtype high-risk samples, most of them carry the mutations of PTEN and/or EGFR , which are the characteristics of primary GBMs. The result is consistent with the telomere replacement extension mechanism discussed in previous studies ( Heaphy et al, 2011 ; Akter and Kamijo, 2021 ; Rachakonda et al, 2021 ; Valenzuela et al, 2021 ). This indicates that our signature is capable of identifying the high-risk samples with either primary or recurrent malignant GBM characteristics.…”

G-Quadruplex Formed by the Promoter Region of the hTERT Gene: Structure-Driven Effects on DNA Mismatch Repair Functions

“…The melting curves of the WT hTERT G4 showed a single-step cooperative transition. It can be assumed that the observed melting curve is a superposition of the melting of three quadruplex units, given that the major form of the multiquadruplex WT hTERT G4 structure corresponds to three stacked parallel G4 units ( Figure 1 ) [ 6 ] that are stabilized by the same number of G-tetrads. In the case of a two-quadruplex model [ 16 ], the stability of each G4 should vary due to the different conformation and topology of the constituent components.…”

“…Functional genetic studies have identified several point mutations within the hTERT core promoter region (approximately −180 to +1 of transcription start site) ( Figure 1 ) [ 5 ]. Mutually exclusive C>T substitutions in the coding hTERT promoter strand occur most frequently at positions −124 bp (position 1295228 of chromosome 5, the mutation is designated as C228T) and −146 bp (position 1295250—C250T) relative to the ATG start codon of the hTERT gene [ 6 ]. These mutations are found in 60–80% of urothelial carcinomas [ 7 ], 71% of melanomas [ 8 ], 83% of glioblastomas [ 9 ], and a variety of other cancers.…”

“…One model features a structure with three parallel G4s interacting with each other via stacking interactions of terminal G-tetrads, while the other represents two stacked individual quadruplexes, including parallel G4 and G4 adopting a mixed (3 + 1) topology with an unusual DNA hairpin formed by the 26-nt loop. According to a recent study, the major form corresponds to three stacked parallel G4 units ( Figure 1 ) [ 6 ].…”