@article{3160728,
    title = "Telomerase Reverse Transcriptase Promoter Mutations in Bladder Cancer:
High Frequency Across Stages, Detection in Urine, and Lack of
Association with Outcome",
    author = "Allory, Yves and Beukers, Willemien and Sagrera, Ana and Flandez, Marta and and Marques, Miriam and Marquez, Mirari and van der Keur, Kirstin A. and and Dyrskjot, Lars and Lurkin, Irene and Vermeij, Marcel and Carrato, and Alfredo and Lloreta, Josep and Lorente, Jose A. and Pau, Enrique and Carrillo-de Santa and Masius, Roy G. and Kogevinas, Manolis and and Steyerberg, Ewout W. and van Tilborg, Angela A. G. and Abas, Cheno and and Orntoft, Torben F. and Zuiverloon, Tahlita C. M. and Malats, Nuria and and Zwarthoff, Ellen C. and Real, Francisco X.",
    journal = "European urology oncology",
    year = "2014",
    volume = "65",
    number = "2",
    pages = "360-366",
    publisher = "Elsevier",
    doi = "10.1016/j.eururo.2013.08.052",
    keywords = "Bladder cancer; TERT gene; Somatic mutations; Clinical end point;
Urine-based diagnosis",
    abstract = "Background: Hotspot mutations in the promoter of the gene coding for
telomerase reverse transcriptase (TERT) have been described and proposed
to activate gene expression.
Objectives: To investigate TERT mutation frequency, spectrum,
association with expression and clinical outcome, and potential for
detection of recurrences in urine in patients with urothelial bladder
cancer (UBC).
Design, setting, and participants: A set of 111 UBCs of different stages
was used to assess TERT promoter mutations by Sanger sequencing and TERT
messenger RNA (mRNA) expression by reverse transcription-quantitative
polymerase chain reaction. The two most frequent mutations were
investigated, using a SNaPshot assay, in an independent set of 184
non-muscle-invasive and 173 muscle-invasive UBC (median follow-up: 53 mo
and 21 mo, respectively). Voided urine from patients with suspicion of
incident UBC (n = 174), or under surveillance after diagnosis of
non-muscle-invasive UBC (n = 194), was tested using a SNaPshot assay.
Outcome measurements and statistical analysis: Association of mutation
status with age, sex, tobacco, stage, grade, fibroblast growth factor
receptor 3 (FGFR3) mutation, progression-free survival, disease-specific
survival, and overall survival.
Results and limitations: In the two series, 78 of 111 (70%) and 283 of
357 (79%) tumors harbored TERT mutations, C228T being the most frequent
substitution (83% for both series). TERT mutations were not associated
with clinical or pathologic parameters, but were more frequent among
FGFR3 mutant tumors (p = 0.0002). There was no association between TERT
mutations and mRNA expression (p = 0.3). Mutations were not associated
with clinical outcome. In urine, TERT mutations had 90% specificity in
subjects with hematuria but no bladder tumor, and 73% in
recurrence-free UBC patients. The sensitivity was 62% in incident and
42% in recurrent UBC. A limitation of the study is its retrospective
nature.
Conclusions: Somatic TERT promoter mutations are an early, highly
prevalent genetic event in UBC and are not associated with TERT mRNA
levels or disease outcomes. A SNaPshot assay in urine may help to detect
UBC recurrences. (C) 2013 European Association of Urology. Published by
Elsevier B. V. All rights reserved."
}