Telomerase Reverse Transcriptase Promoter Mutations in Bladder Cancer:
High Frequency Across Stages, Detection in Urine, and Lack of
Association with Outcome
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
