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TERT promoter mutations and telomerase reactivation in urothelial cancer

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Science  27 Feb 2015:
Vol. 347, Issue 6225, pp. 1006-1010
DOI: 10.1126/science.1260200

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The downstream effects of false promotion

Special DNA sequences at the ends of chromosomes, called telomeres, are replenished by a dedicated enzyme called telomerase. A subset of human tumors harbors mutations in the promoter region of the TERT gene, which codes for a subunit of telomerase. Borah et al. explored the downstream effects of TERT promoter mutations in cells derived from urothelial (urinary tract) cancers. The mutations were associated with aberrantly high levels of TERT mRNA, TERT protein and telomerase activity, and longer telomeres. A small study of clinical samples suggested that high levels of TERT mRNA may be a marker of more aggressive urothelial cancers.

Science, this issue p. 1006

Abstract

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 TERT messenger 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 TERT mRNA 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.

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