In:
Acta Neuropathologica Communications, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2020-12)
Abstract:
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 ( TERT p), i.e. c.1-124 C 〉 T, c.1-146 C 〉 T, confers a proliferative advantage to neoplastic cells. In gliomas, TERT p mutations ( TERT p mut ) mainly occur in oligodendroglioma and glioblastoma. We screened, for TERT p 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 TERT p variants, which consisted of a tandem duplications of 22 nucleotides, i.e. a TERT p c.1-100_1-79dup and TERT p 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 TERT p c.1-100_1-79dup and TERT p c.1-110_1-89, respectively. TERT p duplications ( TERT p dup ) 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 TERT p dup 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 TERT p mut . On the other hand, they were distinguished by enhanced affinity for the Krüppel proteins. The luciferase assay confirmed that TERT p dup behaved as gain-of-function mutations causing a 2,3-2,5 fold increase of TERT transcription. The present study provides new insights into TERT p 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.
Type of Medium:
Online Resource
ISSN:
2051-5960
DOI:
10.1186/s40478-020-01022-4
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2020
detail.hit.zdb_id:
2715589-4
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