Telomerase Reverse Transcriptase Promoter Mutations in Bladder Cancer: High Frequency Across Stages, Detection in Urine, and Lack of Association with Outcome
Telomerase Reverse Transcriptase Promoter Mutations in Bladder Cancer: High Frequency Across Stages, Detection in Urine, and Lack of Association with Outcome
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DOI：
10.1016/j.eururo.2013.08.052
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发表时间：
2014-02-01
期刊：
影响因子：
23.4
通讯作者：
Real, Francisco X.
中科院分区：
文献类型：
--
作者：
Allory, Yves;Beukers, Willemien;Real, Francisco X.
背景资料：端粒酶逆转录酶（telomerase reverse transcriptase，TERT）基因启动子的热点突变已被描述并被提出激活基因expression.Objectives：为了研究端粒酶逆转录酶突变频率、谱、与表达和临床结果的相关性，以及检测尿路上皮膀胱癌（urothelial bladder cancer，UBC）患者尿液中复发的可能性。采用桑格（Sanger）测序法检测111例不同分期的UBC中TERT启动子的突变情况，采用逆转录-定量聚合酶链反应（RT-PCR）检测其TERT信使RNA（mRNA）的表达。两个最常见的突变进行了研究，使用SNaPshot分析，在一个独立的184个非肌肉侵入性和173个肌肉侵入性UBC（中位随访时间：53个月和21个月，分别）。使用SNaPshot测定法测试来自疑似偶发UBC（n = 174）或在诊断为非肌肉侵入性UBC（n = 194）后处于监测下的患者的排尿。突变状态与年龄、性别、烟草、分期、分级、成纤维细胞生长因子受体3（FGFR 3）突变、无进展生存期、疾病特异性生存期、结果和局限性：在两个系列中，111例肿瘤中的78例（70%）和357例肿瘤中的283例（79%）携带TERT突变，C228 T是最常见的取代（两个系列均为83%）。TERT突变与临床或病理参数无关，但在FGFR 3突变肿瘤中更常见（p = 0.0002）。TERT突变和mRNA表达之间没有关联（p = 0.3）。突变与临床结果无关。在尿液中，TERT突变在有血尿但无膀胱肿瘤的受试者中的特异性为90%，在无复发的UBC患者中的特异性为73%。对初发UBC的敏感性为62%，对复发UBC的敏感性为42%。该研究的一个局限性是其回顾性nature.Conclusions：体细胞TERT启动子突变是一个早期的，高度流行的遗传事件在UBC和不相关的TERTmRNA水平或疾病的结果。尿液中的SNaPshot检测可能有助于检测UBC复发。(C)2013年欧洲泌尿外科协会。由Elsevier B出版。V.保留所有权利。
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.