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Eur Urol. 2014 Feb;65(2):360-6. doi: 10.1016/j.eururo.2013.08.052. Epub 2013 Sep 7.

Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome.

Author information

1
Epithelial Carcinogenesis Group, Molecular Pathology Program, CNIO (Spanish National Cancer Research Center), Madrid, Spain; Université Paris-Est Créteil, Institut Mondor de Recherche Biomédicale, Créteil, France.
2
Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
3
Epithelial Carcinogenesis Group, Molecular Pathology Program, CNIO (Spanish National Cancer Research Center), Madrid, Spain.
4
Genetic and Molecular Epidemiology Group, Human Cancer Genetics Program, CNIO (Spanish National Cancer Research Center), Madrid, Spain.
5
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
6
Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain.
7
Department of Pathology, Hospital del Mar-Parc de Salut Mar, Barcelona, Spain; Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
8
Urology Service, Hospital del Mar-Parc de Salut Mar, Barcelona, Spain.
9
Centre de Recerca d'Epidemiologia Ambiental, Barcelona, Spain; IMIM-Institut de Recerca Hospital del Mar, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; National School of Public Health, Athens, Greece.
10
Department of Public Health, Erasmus MC, Rotterdam, The Netherlands.
11
Department of Pathology, Erasmus MC, Rotterdam, The Netherlands; Epithelial Carcinogenesis Group, Molecular Pathology Program, CNIO (Spanish National Cancer Research Center), Madrid, Spain.
12
Epithelial Carcinogenesis Group, Molecular Pathology Program, CNIO (Spanish National Cancer Research Center), Madrid, Spain; Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: preal@cnio.es.

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.

KEYWORDS:

Bladder cancer; Clinical end point; Somatic mutations; TERT gene; Urine-based diagnosis

PMID:
24018021
DOI:
10.1016/j.eururo.2013.08.052
[Indexed for MEDLINE]
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