Department of Neurological Surgery, University of California, San Francisco, CA, USA.
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Nat Commun. 2022 Sep 16;13(1):5430. doi: 10.1038/s41467-022-33099-x.
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 启动子中的突变代表了肿瘤细胞永生化的遗传基础。除了选择性招募 ETS 因子 GABP 来激活 TERT 的两个最常见的点突变外，其他变体的意义尚不清楚。在七种癌症类型中，我们在 TERT 的核心启动子区域内鉴定到野生型序列的重复，这些重复具有惊人的相似特征，包括 ETS 基序、重复长度和插入位点。这些重复通过天然的 ETS 基序及其精确间隔的重复对应物募集 GABP 四聚体，激活启动子，并在 TERT 表达的多灶性胶质母细胞瘤中呈克隆状态。我们得出结论，复发性 TERT 启动子重复在功能和机制上与赋予肿瘤细胞永生化的热点突变等效。这些不同的体细胞遗传改变的共同机制表明，强烈需要募集 GABP 四聚体来激活 TERT。
