TERT C228T mutation in non‐malignant bladder urothelium is associated with intravesical recurrence for patients with non‐muscle invasive bladder cancer

Abstract

Telomerase reverse transcriptase ( TERT ) promoter mutations are frequently found in tumors or urine from patients with urothelial carcinoma (UC). TERT promoter mutations are also detected in urine from patients with no evidence of cancer but are associated with subsequent UC development. Mutations in the TERT promoter are thought to be present in nonmalignant urothelium (NMU) during early stages of tumor formation prior to pathological change, but this has not been proven directly. In this proof‐of‐concept study, we investigated the clinical utility of TERT promoter mutation analysis in NMU of patients with non‐muscle‐invasive bladder cancer (NMIBC). This single‐institute study included 53 primary tumors and 428 systematic bladder biopsy specimens from 54 patients with NMIBC. All patients underwent systematic random biopsy and transurethral resection of the bladder tumor. Genomic DNA was analyzed for TERT C228T and C250T mutations using droplet digital PCR (ddPCR). The association between TERT promoter mutation of NMU and bladder recurrence was examined by the Kaplan–Meier method and Cox proportional hazards model. Of the 54 patients, 16 (29.6%) had a TERT C228T mutation and three (5.6%) had a TERT C250T mutation in NMU. Of 428 biopsy specimens, the TERT C228T mutation was detected in 9% (31/364) of normal urothelium, 27% (4/15) of urothelial dysplasia (UD), 50% (9/18) of UD suspicious for carcinoma in situ (CIS), and 58% (18/31) of CIS. During follow‐up (median: 3.7 years), 22 (40.7%) patients experienced bladder recurrence and five (9.3%) experienced disease progression. Cox proportional hazard analysis showed that TERT C228T mutation in NMU was significantly associated with bladder recurrence after adjustment for cofounding factors ( P = 0.0128). Thus, TERT C228T mutation was detected in NMU, which was a reliable independent prognostic factor of bladder tumor recurrence.

Mutational Landscape and Environmental Effects in Bladder Cancer

“…These mutations are identified in both the normal tissues, which may be precancerous lesion, and the tumor samples of bladder cancer including various rare histological variants (micropapillary, plasmacytoid, adenocarcinoma, squamous cell carcinoma) [ 21 , 22 , 23 , 24 , 25 , 26 ]. These mutations can also be detected with ease in both the pellet and cell-free DNA from patient urine samples, promising application in urine-based disease detection and prediction of progression [ 27 , 28 , 29 , 30 ].…”

TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers

“…With Smoking being the most important risk factor, the proposed induced DNA damage from carcinogens within the urine or blood stream led to the idea of field cancerization but also DNA mutations occurring in non-malignant urothelium [5,12]. This observation was recently reported by Hayashi et al [13] identifying TERT promoter mutations in systematically collected normal urotheliums locating adjacent to non-invasive bladder tumor tissue. Additionally, even when the tumor was not mutated the associated normal urothelium showed a TERT promoter mutation.…”

“…Additionally, even when the tumor was not mutated the associated normal urothelium showed a TERT promoter mutation. Moreover, if TERT mutations were initially observed, positive associations with bladder recurrence after therapy were shown indicating a potential use of TERT promoter gene mutations as a biomarker [ 13 ]. In line with the above findings, in this present study we also identified specific TERT promoter mutations in tumor associated normal urothelium but also in non-invasive urothelial lesions adjacent to or non-adjacent to muscle invasive tumors.…”

Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer

“…Mutations in the core promoter region of TERT cause telomerase reactivation in 60-80% of urothelial bladder tumors 13 . The TERT C228T mutation has been shown to be significantly associated with the prognosis of bladder cancer, particularly with bladder recurrence in NMIBC 14 , whereas TERT C250 mutation appears to be an independent predictive marker of response to BCG treatment 15 . However, in our series, neither C228T nor C250 mutation was associated with prognosis of NMIBC or response to BCG-therapy.…”