TERT Promoter Mutations Detectable 10 Years Prior to Bladder Cancer Diagnosis

This study provides the first evidence of the urinary TERT promoter mutations to be used as simple and cost-effective non-invasive biomarkers for the early detection of bladder cancer.

A study published in EBioMedicine provides the first evidence from a population-based prospective cohort study of the potential of urinary telomerase reverse transcriptase (TERT) promoter mutations to be used as simple and inexpensive non-invasive biomarkers for the early detection of bladder cancer. 

Moreover, the study found that TERT promoter mutations were detectable in urine samples up to 10 years prior to bladder cancer diagnosis, with 100% specificity and 46.7% sensitivity. However, further studies should evaluate the clinical utility of these biomarkers in other longitudinal cohorts.  

“To our knowledge, this study represents the first nested case-control study within a population-based prospective cohort of initially healthy adults which has assessed the predictive value of non-invasive biomarkers for early detection of [bladder cancer] years before the clinical diagnosis,” the authors wrote. “Our pilot study provides the first evidence of the ability of detecting tumor-derived alterations in the urine of asymptomatic individuals who subsequently developed [bladder cancer].” 

Performing a nested case-control study, the researchers used the population-based prospective Golestan Cohort Study, consisting of 50,045 participants followed up to 14 years, and assessed TERT promoter mutations in baseline urine samples from 38 asymptomatic individuals who later developed primary bladder cancer and 152 matched controls. 

After obtaining the results for 30 cases and 101 controls from the, TERT promoter mutations were found in 14 of the pre-clinical cases (sensitivity 46.67%) and none of the controls (100%). At an estimated bladder cancer cumulative incidence of 0.09% in the participants, the positive and negative predictive values were 100% and 99.95%, respectively. Additionally, the mutant allelic fractions decreased with the time interval from urine collection until bladder cancer diagnosis (= 0.033), however the mutations were detectable up to 10 years before the clinical diagnosis. 

“The most striking findings in this study were the detection of TERT promoter mutations in urine collected up to 10 years before clinical [bladder cancer] diagnosis and the lack of false positive results in any of the controls,” the authors wrote. “This suggests a very slow tumorigenic process in at least some TERT-mutated [bladder cancers], which could provide a window of opportunity for early molecular detection and intervention.”

Additionally, the researchers noted that the data presented suggests that longitudinal studies with inadequate follow-up periods may not be able to assess the true specificity of these individuals, given that individuals who test positive and have no current evidence of bladder cancer could still be diagnosed with clinical bladder cancer after a longer follow-up duration.

However, the results should be interpreted with caution, given that only 101 controls were tested and those with a history of any cancer were not included in the evaluation as controls. Therefore, though the true specificity of these biomarkers for bladder cancer might be very high, including high enough to be clinically useful for bladder cancer screening, the researchers suggested that the specificity of the biomarkers should be further evaluated in a large series of controls unselected for other cancer diagnosis. 

According to the study, approximately 549,000 individuals were diagnosed with bladder cancer across the world in 2018, and 200,000 died as a result of the disease. Furthermore, in the US and Iran, bladder cancer is the fourth most common cancer diagnosed in men. 


Hosen I, Sheikh M, Zvereva M, et al. Urinary TERT promoter mutations are detectable up to 10 years prior to clinical diagnosis of bladder cancer: Evidence from the Golestan Cohort Study.