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.

中文翻译：

---

在膀胱癌临床诊断前 10 年即可检测到尿液 TERT 启动子突变：来自 Golestan 队列研究的证据。


背景技术使用尿液生物标志物检测临床前膀胱癌（BC）可以为筛查和管理提供宝贵的机会。尿液中可检测到的端粒酶逆转录酶 (TERT) 启动子突变已成为有前途的 BC 生物标志物。方法 我们在基于人群的前瞻性 Golestan 队列研究（50,045 名参与者，随访长达 14 年）中进行了一项巢式病例对照研究，并评估了 38 名后来发展为原发性 BC 的无症状个体和 152 名匹配对照者的基线尿液样本中的 TERT 启动子突变。使用基于下一代测序的单重测定 (UroMuTERT) 和液滴数字 PCR 测定。结果 获得了 30 例病例和 101 例对照的结果。在 14 例临床前病例中检测到 TERT 启动子突变（敏感性 46·67%），而对照组则没有检测到突变（特异性 100·00%）。在队列中估计 BC 累积发生率为 0·09% 时，阳性和阴性预测值分别为 100·00% 和 99·95%。突变等位基因分数随着从尿液收集到 BC 诊断的时间间隔而减少 (p = 0·033)，但突变在临床诊断前 10 年即可检测到。解释 我们的结果提供了基于人群的前瞻性队列研究的第一个证据，证明尿 TERT 启动子突变作为 BC 早期检测的有希望的非侵入性生物标志物的潜力。进一步的研究应该验证这一发现并评估其在其他纵向队列中的临床效用。资助法国癌症联盟、世界癌症研究基金会国际、英国癌症研究中心、德黑兰医科大学、国际癌症研究机构和美国国家癌症研究所。