Mutations in the TERT promoter represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants is unknown. In seven cancer types, we identify duplications of wildtype sequence within the core promoter region of TERT that have strikingly similar features including an ETS motif, the duplication length and insertion site. The duplications recruit a GABP tetramer by virtue of the native ETS motif and its precisely spaced duplicated counterpart, activate the promoter and are clonal in a TERT expressing multifocal glioblastoma. We conclude that recurrent TERT promoter duplications are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.

TERT启动子的突变代表了肿瘤细胞永生的遗传基础。除了两种最常见的点突变（选择性招募 ETS 因子 GABP 来激活TERT）之外，其他变异的意义尚不清楚。在七种癌症类型中，我们鉴定了TERT核心启动子区域内野生型序列的重复，它们具有惊人相似的特征，包括 ETS 基序、重复长度和插入位点。复制凭借天然 ETS 基序及其精确间隔的复制对应物招募 GABP 四聚体，激活启动子并在表达TERT的多灶性胶质母细胞瘤中克隆。我们得出的结论是，反复出现的TERT启动子重复在功能和机制上与赋予肿瘤细胞永生性的热点突变相同。这些不同体细胞遗传改变的共同机制表明，招募 GABP 四聚体以激活TERT存在强大的选择压力。