The catalytic activity of human Telomerase Reverse Transcriptase (TERT) compensates for the loss of telomere length, eroded during each cell cycle, to ensure a correct division of stem and germinal cells. In human tumors, ectopic TERT reactivation, most frequently due to hotspot mutations in the promoter region (TERTp), i.e. c.1-124 C > T, c.1-146 C > T, confers a proliferative advantage to neoplastic cells. In gliomas, TERTp mutations (TERTpmut) mainly occur in oligodendroglioma and glioblastoma. We screened, for TERTp hotspot mutations, 301 adult patients with gliomas and identified heterozygous mutations in 239 cases: 94% of oligodendroglioma, 85% of glioblastoma, and 37.5% of diffuse/anaplastic astrocytoma. Besides the recurrent c.1-124 C > T and c.1-146 C > T, two cases of glioblastoma harbored novel somatic TERTp variants, which consisted of a tandem duplications of 22 nucleotides, i.e. a TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, both located downstream c.1-124 C > T and c.1-146 C > T. In silico analysis predicted the formation of 119 and 108 new transcription factor’s recognition sites for TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, respectively. TERTp duplications (TERTpdup) mainly affected the binding capacity of two transcription factors’ families, i.e. the members of the E-twenty-six and the Specificity Protein/Krüppel-Like Factor groups. In fact, these new TERTpdup significantly enhanced the E-twenty-six transcription factors’ binding capacity, which is also typically increased by the two c.1-124 C > T/c.1-146 C > T hotspot TERTpmut. On the other hand, they were distinguished by enhanced affinity for the Krüppel proteins. The luciferase assay confirmed that TERTpdup behaved as gain-of-function mutations causing a 2,3-2,5 fold increase of TERT transcription. The present study provides new insights into TERTp mutational spectrum occurring in central nervous system tumors, with the identification of new recurrent somatic gain-of-function mutations, occurring in 0.8% of glioblastoma IDH-wildtype.

中文翻译：

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新的体细胞TERT启动子变体增强了胶质母细胞瘤中的端粒酶活性。

人端粒酶逆转录酶（TERT）的催化活性可补偿端粒长度的损失，端粒长度在每个细胞周期中都会受到侵蚀，从而确保干细胞和生发细胞的正确分裂。在人类肿瘤中，异位TERT激活最常见，这是由于启动子区域（TERTp）中的热点突变（iec1-124 C> T，c.1-146 C> T）引起的，对肿瘤细胞具有增殖优势。在神经胶质瘤中，TERTp突变（TERTpmut）主要发生在少突胶质细胞瘤和胶质母细胞瘤中。我们筛选了301例成人神经胶质瘤患者的TERTp热点突变，并在239例病例中发现了杂合突变：94％的少突胶质细胞瘤，85％的胶质母细胞瘤和37.5％的弥漫/间变性星形细胞瘤。除了复发的c.1-124 C> T和c.1-146 C> T，还有2例胶质母细胞瘤还携带了新型体细胞TERTp变体，由串联重复的22个核苷酸组成，即TERTp c.1-100_1-79dup和TERTp c.1-110_1-89，均位于c.1-124 C> T和c.1-146 C> T下游在计算机分析中预测分别为TERTp c.1-100_1-79dup和TERTp c.1-110_1-89形成119和108个新的转录因子识别位点。TERTp重复（TERTpdup）主要影响两个转录因子家族的结合能力，即E-26和特异蛋白/Krüppel-Like因子组的成员。实际上，这些新的TERTpdup显着增强了E-26转录因子的结合能力，通常两个c.1-124 C> T / c.1-146 C> T热点TERTpmut也增加了这些结合能力。另一方面，它们以对Krüppel蛋白的亲和力增强而著称。荧光素酶测定法证实TERTpdup表现为功能获得性突变，导致TERT转录增加了2,3-2,5倍。本研究提供了对中枢神经系统肿瘤中发生的TERTp突变谱的新见解，并鉴定了在0.8％的胶质母细胞瘤IDH野生型中发生的新的复发性体细胞功能获得性突变。