TERT promoter mutations and telomerase reactivation in urothelial cancer

Reactivation of telomerase, the chromosome end-replicating enzyme, drives human cell immortality and cancer. Point mutations in the telomerase reverse transcriptase (TERT) gene promoter occur at high frequency in multiple cancers, including urothelial cancer (UC), but their effect on telomerase function has been unclear. In a study of 23 human UC cell lines, we show that these promoter mutations correlate with higher levels of TERTmessenger RNA (mRNA), TERT protein, telomerase enzymatic activity, and telomere length. Although previous studies found no relation between TERT promoter mutations and UC patient outcome, we find that elevated TERTmRNA expression strongly correlates with reduced disease-specific survival in two independent UC patient cohorts (n = 35; n = 87).These results suggest that high telomerase activity may be a better marker of aggressive UC tumors than TERT promoter mutations alone.