Clinical Application of TERT Promoter Mutations in Urothelial Carcinoma

Abstract

Urothelial carcinoma (UC) is a common urological malignancy with a high rate of disease recurrence. Telomerase activity, a hallmark of cancer characterized by overcoming the replicative senescence, is upregulated in over 90% of patients with UC. Somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) are frequently detected in UC, and drive telomerase activity. Recent studies have demonstrated a strong association between TERT promoter mutation and tumorigenesis of UC. Also, TERT promoter mutation has great potential for diagnosis, as well as prognosis in UC treatment, and this is also applicable for the liquid biopsy techniques. In this review, we discuss the progress in these areas and highlight the challenges, clinical potential, and future direction for developing UC treatment methods.

TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance

“…The identification of prevalent TERT promoter mutation/methylation in UC tumors, together with their absence in almost all (truly) normal urothelial tissues, suggest that they may serve as ideal urinary biomarkers for UC diagnostics. Indeed, clinical studies have shown detectable C228T and C250T mutations in urine from patients with UC, which is highly consistent with their presence in patient tumors ( 37 – 41 , 43 , 44 , 49 , 83 , 84 ). These findings demonstrate the feasibility of urinary TERT promoter assays as the UC diagnostic biomarker.…”

“…Cystoscopy and urinary cytology are routinely applied for UCB and/or UTUC diagnostics ( 49 , 82 ). In addition, a life-long surveillance of patients is recommended due to frequent recurrence.…”

“…Two hotspot mutations occur at the proximal region of the TERT promoter (−124 and −146 bp from the ATG) with a cytidine-tothymidine (C>T) dipyrimidine transition, which are called as C228T (-124C>T) and C250T (-146C>T), respectively (31,32). Across UC subtypes, the frequency of TERT promoter mutations is different, varying from less than 20% in UCU, 45% in UCRPs, to ~85% in UCBs (28,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49). The C228T mutation is predominant and the presence of C228T and C250T is mutually exclusive, indicating a functional redundancy of these two mutations (Figure 2).…”

“…The TERT promoter mutation and methylation or TERT transcripts as urinary biomarkers for UC diagnosis and disease surveillance Cystoscopy and urinary cytology are routinely applied for UCB and/or UTUC diagnostics (49,82). In addition, a life-long surveillance of patients is recommended due to frequent recurrence.…”

Urinary Exosomal Long Noncoding RNA TERC as a Noninvasive Diagnostic and Prognostic Biomarker for Bladder Urothelial Carcinoma

“…The important components of the telomerase are TERT and TERC . As previously reported, identifying TERT promoter mutations in the urine may substantially aid in the early detection of bladder cancer [ 29 , 30 ]. However, exosomal TERC has thus far not been investigated as a diagnostic or prognostic biomarker for bladder cancer.…”