Hayashi Y, et al. Mol Oncol 2020.
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 non-malignant urothelium 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 non-malignant urothelium 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 polymerase chain reaction. The association between TERT promoter mutation of non-malignant urothelium 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 non-malignant urothelium. Of 428 biopsy specimens, the TERT C228T mutation was detected in 9% (31/364) of normal urothelium, 27％ (4/15) of urothelial dysplasia, 50% (9/18) of urothelial dysplasia 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 5 (9.3%) experienced disease progression. Cox proportional hazard analysis showed that TERT C228T mutation in non-malignant urothelium was significantly associated with bladder recurrence after adjustment for cofounding factors (p = 0.0128). Thus, TERT C228T mutation was detected in non-malignant urothelium, which was a reliable independent prognostic factor of bladder tumor recurrence.