TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance

Abstract

Telomerase, an RNA-dependent DNA polymerase synthesizing telomeric TTAGGG sequences, is primarily silent in normal human urothelial cells (NHUCs), but widely activated in urothelial cell-derived carcinomas or urothelial carcinomas (UCs) including UC of the bladder (UCB) and upper track UC (UTUC). Telomerase activation for telomere maintenance is required for the UC development and progression, and the key underlying mechanism is the transcriptional de-repression of the telomerase reverse transcriptase (TERT), a gene encoding the rate-limiting, telomerase catalytic component. Recent mechanistic explorations have revealed important roles for TERT promoter mutations and aberrant methylation in activation of TERT transcription and telomerase in UCs. Moreover, these TERT-featured genomic and epigenetic alterations have been evaluated for their usefulness in non-invasive UC diagnostics, recurrence monitoring, outcome prediction and response to treatments such as immunotherapy. Importantly, the detection of the mutated TERT promoter and TERT mRNA as urinary biomarkers holds great promise for urine-based UC liquid biopsy. In the present article, we review recent mechanistic insights into altered TERT promoter-mediated telomerase activation in UCs and discuss potential clinical implications. Specifically, we compare differences in senescence and transformation between NHUCs and other types of epithelial cells, address the interaction between TERT promoter mutations and other factors to affect UC progression and outcomes, evaluate the impact of TERT promoter mutations and TERT-mediated activation of human endogenous retrovirus genes on UC immunotherapy including Bacillus Calmette-Guérin therapy and immune checkpoint inhibitors. Finally, we suggest the standardization of a TERT assay and evaluation system for UC clinical practice.

High DNA methylation age deceleration defines an aggressive phenotype with immunoexclusion environments in endometrial carcinoma

“…More recently, aging- and cancer-related hypomethylation has been shown to induce reactivation of HERV gene transcription ( 34 , 51 , 52 ). The ERV-derived products are recognized as “non-self” by the host’s innate and adaptive immune system ( 34 , 53 ). Importantly, transcribed viral double-strand RNAs (dsRNAs), RNA : DNA hybrid, and DNA or cDNA all trigger strong innate immune responses through the activation of pathogen recognition receptors ( 53 ).…”

hTERT gene methylation in circulating DNA, tumor, and surrounding tissue in breast cancer: a prospective study

“…During mastectomy, sections measuring approximately 1 cm 3 were collected from the tumor and surrounding tissue of each patient for DNA analysis. In addition, 5 ml of peripheral blood was collected to analyze cfDNA.…”

“… 1 , 2 Human telomerase reverse transcriptase(hTERT) is an enzyme that synthesizes telomeric DNA sequences. 3 The hTERT enzyme is encoded by the hTERT gene and contains both a protein component and a ribonucleic acidcomponent. 2 The hTERT gene is not expressed in normal postnatal somatic cells, but its expression is elevated in stem, germ, and cancer cells.…”

The cuproptosis-associated 11 gene signature as a predictor for outcomes and response to Bacillus Calmette-Guerin and immune checkpoint inhibitor therapies in bladder carcinoma

“…By targeting PD-1/PD-L1, CTLA4, or other immune checkpoint proteins, the ICI therapy demonstrates robust efficacy in subsets of BLCA patients ( 3 , 9 ). To improve stratification for better immunotherapeutic applications, numerous studies have paid great attention to biomarker identification for response to ICIs ( 3 , 8 , 11 – 15 ). Attempts to look for BCG treatment predictors are far behind, and the evaluation of BCG response depends mainly on cystoscopy, cytology and/or bladder biopsy nowadays ( 8 ), although several molecules are shown to serve as potential factors ( 16 ).…”