Occurrence, functionality, and abundance of theTERTpromoter 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 rejuvenation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene define a definite method for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate surge in TERT transcription and telomerase rejuvenation 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 and publications have resolved the discrete aspects, effects, and clinical relevance of the TERT promoter mutations. Those noncoding alterations link the TERT transcription 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 and the evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.

CTNNB1 mutations, TERT polymorphism and CD8+ cell densities in resected hepatocellular carcinoma are associated with longer time to recurrence

“…The associations were not significant for the AG heterozygotes. Presence of G allele modulated effect of TERTp mutations because the SNP destroys the pre-existing binding site for transcription factors EST [ 36 ]. Our data on the association of this SNP with favourable patient outcome are in agreement with prognostic data for various cancers [ 37 ].…”

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

“…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].…”

“…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.…”

Mutations in the telomerase reverse transcriptase promoter and PIK3CA gene are common events in penile squamous cell carcinoma of Italian and Ugandan patients

“…Telomerase expression is reactivated in the majority of tumours through several mechanisms, including chromosomal rearrangements, gene amplification, virus integration and TERT promoter methylation. 36,37 In addition, in HPV-related tumours, such as cervical neoplasia, the E6 oncoprotein encoded by high risk HPVs has shown to potentiate the telomerase activity either by the transactivation of TERT promoter or through the physical and functional interaction with the telomerase complex thus driving the limitless proliferation of undifferentiated epithelial cells. [38][39][40] The discovery of hotspot mutations in the core promoter of the TERT gene represents a new mechanism of irreversible activation of telomerase in many tumour types and in particular in those arising from tissues with a low rate of selfrenewal.…”