Evidence before this study

The best hope for reducing bladder cancer (BC) mortality and morbidity remains early detection and subsequent surgical excision of non-muscle invasive bladder tumours. Despite the routine use of urine cytology and commercialization of several FDA-approved urine biomarkers for bladder cancer management, these methods do not offer the combined sensitivity and specificity needed to be clinically useful for bladder cancer detection, especially for early stage tumours. Telomerase reverse transcriptase (TERT) promoter mutations are the most frequent genetic alterations occurring in bladder cancer. They are equally distributed across different grades and stages of the disease and are reported to be early events in carcinogenesis. We and others have previously shown that TERT promoter mutations are detectable in urinary DNA from the exfoliated cells of bladder epithelium or in urinary cell-free DNA. We specifically have shown that TERT promoter mutations detected in urinary DNA by our simple, single-plex assay (UroMuTERT) have excellent sensitivity and specificity for the detection of all forms of urothelial cancer of the bladder, significantly outperforming that of urine cytology, especially for the detection of low-grade and/or early stage urothelial cancers.

The ability to detect these mutations in pre-diagnostic urine samples has enormous potential as a non-invasive tool for early detection and potentially cost-effective screening of high-risk individuals. We searched PubMed with terms “TERT promoter mutations”, “urine”, “blood”, “liquid biopsy”, “bladder cancer”, “urothelial cancer” “screening of bladder/urothelial cancer” and “urinary biomarker” for studies published between January 2006 and December 2018. No study has shown the detectability of a biomarker years prior diagnosis of bladder cancer in asymptomatic individuals.

Added value of this study

Building on our promising earlier studies of the non-invasive UroMuTERT assay, we investigated the potential of urinary TERT promoter mutations as an early detection biomarker for bladder cancer in asymptomatic individuals in a case-control study nested within a longitudinal population-based prospective cohort of 50,045 Iranian individuals. This is the first study showing that tumour-derived TERT promoter mutations could be detected in urine samples up to 10 years prior to the primary diagnosis of bladder cancer and were absent among matched controls who did not develop any cancer in the 10 years after sample collection. This pilot study also provides the first evaluation of a urinary biomarker in a population-based prospective cohort study and the first evidence of the ability of urinary TERT promoter mutations to detect pre-clinical bladder cancer.

Implications of all the available evidence

Our prospective pilot study demonstrates the potential of urinary TERT promoter mutations as early biomarkers for bladder cancer and brings them a step further in the validation phases of biomarker development for early detection. Both the high specificity of these biomarkers and their detection up to 10 years before clinical diagnosis of bladder cancer suggest great potential for clinical utility for early detection of pre-clinical tumours and possibly for surveillance of patients for disease recurrence. If the current findings are validated in other long-term population-based prospective cohorts, large prospective randomized controlled trials in high-risk cohorts should be designed to address the health and cost benefits of TERT promoter mutations screening on the global bladder cancer burden. As part of the integration of these biomarkers into BC screening and clinical management, test-positive individuals could be offered investigation with cystoscopy or urography for early clinical diagnosis and then triaged to treatment or a surveillance program, as appropriate.