Cancer. 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 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.
Howard Hughes Medical Institute, University of Colorado BioFrontiers Institute, Boulder, CO 80309, USA. Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
Sumit
S
Borah
Howard Hughes Medical Institute, University of Colorado BioFrontiers Institute, Boulder, CO 80309, USA. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
Linghe
L
Xi
Howard Hughes Medical Institute, University of Colorado BioFrontiers Institute, Boulder, CO 80309, USA. Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
Arthur J
AJ
Zaug
Howard Hughes Medical Institute, University of Colorado BioFrontiers Institute, Boulder, CO 80309, USA. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
Natasha M
NM
Powell
Department of Mathematics and Computer Science, Eastern Connecticut State University, Willimantic, CT 06226, USA.
Garrett M
GM
Dancik
Children's Medical Research Institute and University of Sydney, Westmead, NSW 2145, Australia.
Scott B
SB
Cohen
University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA. Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
James C
JC
Costello
University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA. Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Department of Surgery, University of Colorado, Aurora, CO 80045, USA.
Dan
D
Theodorescu
Howard Hughes Medical Institute, University of Colorado BioFrontiers Institute, Boulder, CO 80309, USA. Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA. University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA. thomas.cech@colorado.edu.
Thomas R
TR
Cech
D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*; D059505:Telomere Homeostasis; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000201:enzymology / Q000473:pathology
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C509186:TERT protein, human; D019098:Telomerase