title: TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine.
abstract: Activating mutations occur in the promoter of the telomerase reverse transcriptase (TERT) gene in 66% of muscle-invasive urothelial carcinomas. To explore their role in bladder cancer development and to assess their utility as urine markers for early detection, we sequenced the TERT promoter in 76 well-characterized papillary and flat noninvasive urothelial carcinomas, including 28 pTa low-grade transitional cell carcinomas (TCC), 31 pTa high-grade TCCs, and 17 pTis carcinoma in situ lesions. We also evaluated the sequence of the TERT promoter in a separate series of 14 early bladder neoplasms and matched follow-up urine samples to determine whether urine TERT status was an indicator of disease recurrence. A high rate of TERT promoter mutation was observed in both papillary and flat lesions, as well as in low- and high-grade noninvasive urothelial neoplasms (mean: 74%). In addition, among patients whose tumors harbored TERT promoter mutations, the same mutations were present in follow-up urines in seven of eight patients that recurred but in none of the six patients that did not recur (P < 0.001). TERT promoter mutations occur in both papillary and flat lesions, are the most frequent genetic alterations identified to date in noninvasive precursor lesions of the bladder, are detectable in urine, and seem to be strongly associated with bladder cancer recurrence. These provocative results suggest that TERT promoter mutations may offer a useful urinary biomarker for both early detection and monitoring of bladder neoplasia.
authors.affiliation: Authors' Affiliations: The Ludwig Center for Cancer Genetics and Therapeutics, The Swim Across America Laboratory at Johns Hopkins, and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center; Departments of Pathology, Oncology, and Urology, The Johns Hopkins Medical Institutes, Baltimore, Maryland.
authors.forename: Isaac
authors.initials: I
authors.lastname: Kinde
authors.forename: Enrico
authors.initials: E
authors.lastname: Munari
authors.forename: Sheila F
authors.initials: SF
authors.lastname: Faraj
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Mark
authors.initials: M
authors.lastname: Schoenberg
authors.forename: Trinity
authors.initials: T
authors.lastname: Bivalacqua
authors.forename: Mohamad
authors.initials: M
authors.lastname: Allaf
authors.forename: Simeon
authors.initials: S
authors.lastname: Springer
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000652:urine*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology / Q000652:urine*; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000652:urine*
chemical_list: D014408:Biomarkers, Tumor; C509186:TERT protein, human; D019098:Telomerase