TERT promoter mutations correlate with high TERT and telomerase reactivation in urothelial cancer.
Major finding: TERT promoter mutations correlate with high TERT and telomerase reactivation in urothelial cancer.
Clinical relevance: Increased TERT mRNA expression is associated with decreased disease-specific survival.
Impact: Elevated TERT expression, rather than TERT promoter mutations, may be a better prognostic marker.
Telomerase is a ribonucleoprotein enzyme that plays a critical role in maintaining the stability of chromosome ends and is reactivated in the majority of human cancers to facilitate uncontrolled tumor cell proliferation. Point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene, which encodes the catalytic subunit of telomerase, frequently occur in various types of cancer, including melanoma and urothelial carcinoma, resulting in the formation of ETS transcription factor binding sites that may promote increased TERT transcription. TERT promoter mutations have been implicated as a potential mechanism to reactivate telomerase activity in cancer cells; however, previous studies have not found a correlation between these mutations and patient outcome in urothelial carcinoma, and the effect of these mutations on telomerase function remains poorly understood. Using a panel of 23 urothelial carcinoma cell lines, Borah, Xi, Zaug, and colleagues found that cells harboring TERT promoter mutations often exhibited an increase in TERT mRNA and protein levels. This increase in TERT expression was strongly associated with elevated telomerase enzymatic activity and longer telomere lengths in urothelial carcinoma cell lines with TERT promoter mutations. In addition, although not all mutant cells exhibited increased telomerase activity, the cell lines with the highest TERT expression and telomerase activity harbored TERT promoter mutations. Importantly, analysis of two independent patient cohorts revealed that increased TERT mRNA expression correlated with decreased disease-specific survival in urothelial carcinoma, suggesting that TERT expression levels may represent a better prognostic biomarker than TERT promoter mutations. These findings support the notion that TERT promoter mutations result in high-level TERT reactivation in urothelial carcinoma, and suggest that targeted inhibition of telomerase may be beneficial in urothelial tumors with increased telomerase activity.