膀胱癌中端粒酶逆转录酶启动子突变：跨越多个阶段的高频率、尿液中的检测以及与结局无关。

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

机构信息

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.

Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.

出版信息

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

DOI:10.1016/j.eururo.2013.08.052

PMID:24018021

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.

摘要

背景

端粒酶逆转录酶（TERT）基因编码区启动子热点突变已被描述，并被提议激活基因表达。

目的

研究 TERT 突变频率、谱、与表达和临床结局的关系，以及在尿中检测尿路上皮膀胱癌（UBC）复发的可能性。

设计、设置和参与者：一组 111 例不同分期的 UBC 用于通过 Sanger 测序评估 TERT 启动子突变，并通过逆转录定量聚合酶链反应（RT-qPCR）评估 TERT 信使 RNA（mRNA）表达。使用 SNaPshot 分析，对 184 例非肌肉浸润性和 173 例肌肉浸润性 UBC 中的两个最常见突变进行了调查（中位随访时间分别为 53 个月和 21 个月）。对疑似患有 UBC 的患者（n=174）或在诊断为非肌肉浸润性 UBC 后进行监测的患者（n=194）的尿液进行了 SNaPshot 分析。

观察指标和统计分析

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（FGFR3）突变、无进展生存率、疾病特异性生存率和总生存率的关系。

结果和局限性

在两个系列中，111 例肿瘤中有 78 例（70%）和 357 例肿瘤中有 283 例（79%）存在 TERT 突变，C228T 是最常见的取代物（两个系列均为 83%）。TERT 突变与临床或病理参数无关，但在 FGFR3 突变肿瘤中更为常见（p=0.0002）。TERT 突变与 mRNA 表达无关（p=0.3）。突变与临床结局无关。在尿液中，TERT 突变在血尿但无膀胱肿瘤的患者中具有 90%的特异性，在无复发 UBC 患者中具有 73%的特异性。敏感性在新发 UBC 患者中为 62%，在复发性 UBC 患者中为 42%。本研究的局限性在于其回顾性。