Urinary TERT promoter mutations are detectable up to 10 years prior to clinical diagnosis of bladder cancer: Evidence from the Golestan Cohort Study

EBioMedicine. 2020 Mar;53:102643. doi: 10.1016/j.ebiom.2020.102643. Epub 2020 Feb 17.


Background: Detecting pre-clinical bladder cancer (BC) using urinary biomarkers may provide a valuable opportunity for screening and management. Telomerase reverse transcriptase (TERT) promoter mutations detectable in urine have emerged as promising BC biomarkers.

Methods: We performed a nested case-control study within the population-based prospective Golestan Cohort Study (50,045 participants, followed up to 14 years) and assessed TERT promoter mutations in baseline urine samples from 38 asymptomatic individuals who subsequently developed primary BC and 152 matched controls using a Next-Generation Sequencing-based single-plex assay (UroMuTERT) and droplet digital PCR assays.

Findings: Results were obtained for 30 cases and 101 controls. TERT promoter mutations were detected in 14 pre-clinical cases (sensitivity 46·67%) and none of the controls (specificity 100·00%). At an estimated BC cumulative incidence of 0·09% in the cohort, the positive and negative predictive values were 100·00% and 99·95% respectively. The mutant allelic fractions decreased with the time interval from urine collection until BC diagnosis (p = 0·033) but the mutations were detectable up to 10 years prior to clinical diagnosis.

Interpretation: Our results provide the first evidence from a population-based prospective cohort study of the potential of urinary TERT promoter mutations as promising non-invasive biomarkers for early detection of BC. Further studies should validate this finding and assess their clinical utility in other longitudinal cohorts.

Funding: French Cancer League, World Cancer Research Fund International, Cancer Research UK, Tehran University of Medical Sciences, the International Agency for Research on Cancer, and the U.S. National Cancer Institute.

Keywords: Bladder cancer; Early detection; Prospective cohort; TERT promoter mutations; Urinary biomarker.

Publication types

  • Evaluation Study

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / standards
  • Biomarkers, Tumor / urine
  • Cohort Studies
  • Early Diagnosis
  • Female
  • Genetic Testing / standards*
  • Genetic Testing / statistics & numerical data
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Promoter Regions, Genetic
  • Telomerase / genetics*
  • Urinary Bladder Neoplasms / diagnosis*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / urine


  • Biomarkers, Tumor
  • TERT protein, human
  • Telomerase