Activating Telomerase TERT Promoter Mutations and Their Application for the Detection of Bladder Cancer.

Maria Zvereva,Thorsten Ecke,Eduard Pisarev,Alexander Tivtikyan,David Kamalov,Armais Kamalov,Emmanuel Vian,Olga Kisil,Elena Kubareva,Simon Matskeplishvili,Ismail Hosen,Arnaud Manel,Florence Le Calvez-Kelm

doi:10.3390/ijms21176034

Abstract

This review summarizes state-of-the-art knowledge in early-generation and novel urine biomarkers targeting the telomerase pathway for the detection and follow-up of bladder cancer (BC). The limitations of the assays detecting telomerase reactivation are discussed and the potential of transcription-activating mutations in the promoter of the TERT gene detected in the urine as promising simple non-invasive BC biomarkers is highlighted. Studies have shown good sensitivity and specificity of the urinary TERT promoter mutations in case-control studies and, more recently, in a pilot prospective cohort study, where the marker was detected up to 10 years prior to clinical diagnosis. However, large prospective cohort studies and intervention studies are required to fully validate their robustness and assess their clinical utility. Furthermore, it may be interesting to evaluate whether the clinical performance of urinary TERT promoter mutations could increase when combined with other simple urinary biomarkers. Finally, different approaches for assessment of TERT promoter mutations in urine samples are presented together with technical challenges, thus highlighting the need of careful technological validation and standardization of laboratory methods prior to translation into clinical practice.

Highlights

More than 300 thousand new cases of bladder cancer (BC) are diagnosed in the world annually [1]
The absence of urine biomarkers that can be clinically exploited and the fact that the re-activation of telomerase is a crucial mechanism of urothelial carcinogenesis rekindled the interest in further research on other markers indirectly influencing telomerase activation, for example, through recurrent genetic changes that have been identified in the regulatory elements of the telomerase reverse transcriptase (TERT) gene
The fact that TERT promoter mutations have been identified in urine years prior to the primary clinical diagnosis of BC and in some relapse-free patients under surveillance reflects the early occurrence of the mutations in the primary carcinogenic and in the relapse processes, providing a window of opportunity for early molecular detection and intervention

Summary

Introduction

More than 300 thousand new cases of bladder cancer (BC) are diagnosed in the world annually [1]. Preliminary findings indicate a high specificity in cellular models and in few healthy individuals and patients with malignancies other than bladder cancer [24,25,26], but this needs to be confirmed in large case-control studies Another existing method to analyze telomerase reactivation is the quantitative measurement of the expression level of telomerase subunits TERT and telomerase RNA (TR) using real-time reverse transcription polymerase chain reaction (qRT-PCR). High expressions of these mRNAs have been observed consistently across many different malignancies, suggesting a promising avenue for early cancer detection in body fluids, especially in urine samples of patients with BC [27]. The absence of urine biomarkers that can be clinically exploited and the fact that the re-activation of telomerase is a crucial mechanism of urothelial carcinogenesis (observed in 99% of urothelial carcinomas) rekindled the interest in further research on other markers indirectly influencing telomerase activation, for example, through recurrent genetic changes that have been identified in the regulatory elements of the TERT gene

TERT Promoter Mutations and Biological Significance in Bladder Carcinogenesis

Analytical Methods for Detecting Mutations in the TERT Promoter

Method

Predictive Significance of Determining TERT Promoter Mutations in Urine

Findings

Conclusions