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, ectopicTERTreactivation, 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 (TERTp(mut)) mainly occur in oligodendroglioma and glioblastoma. We screened, forTERTp 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 somaticTERTp variants, which consisted of a tandem duplications of 22 nucleotides, i.e. aTERTp c.1-100_1-79dup andTERTp 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 forTERTp c.1-100_1-79dup andTERTp c.1-110_1-89, respectively.TERTp duplications (TERTp(dup)) mainly affected the binding capacity of two transcription factors' families, i.e. the members of the E-twenty-six and the Specificity Protein/Kruppel-Like Factor groups. In fact, these newTERTp(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 hotspotTERTp(mut). On the other hand, they were distinguished by enhanced affinity for the Kruppel proteins. The luciferase assay confirmed thatTERTp(dup)behaved as gain-of-function mutations causing a 2,3-2,5 fold increase ofTERTtranscription. The present study provides new insights intoTERTp mutational spectrum occurring in central nervous system tumors, with the identification of new recurrent somatic gain-of-function mutations, occurring in 0.8% of glioblastomaIDH-wildtype.
New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma
Tiziana Pierini;Carlotta Nardelli;Anair Graciela Lema Fernandez;Fabrizia Pellanera;Valeria Nofrini;Paolo Gorello;Silvia Arniani;Marco Lupattelli;Giulio Metro;Stefano Ascani;Cristina Mecucci;Roberta La Starza
2020
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, ectopicTERTreactivation, 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 (TERTp(mut)) mainly occur in oligodendroglioma and glioblastoma. We screened, forTERTp 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 somaticTERTp variants, which consisted of a tandem duplications of 22 nucleotides, i.e. aTERTp c.1-100_1-79dup andTERTp 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 forTERTp c.1-100_1-79dup andTERTp c.1-110_1-89, respectively.TERTp duplications (TERTp(dup)) mainly affected the binding capacity of two transcription factors' families, i.e. the members of the E-twenty-six and the Specificity Protein/Kruppel-Like Factor groups. In fact, these newTERTp(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 hotspotTERTp(mut). On the other hand, they were distinguished by enhanced affinity for the Kruppel proteins. The luciferase assay confirmed thatTERTp(dup)behaved as gain-of-function mutations causing a 2,3-2,5 fold increase ofTERTtranscription. The present study provides new insights intoTERTp mutational spectrum occurring in central nervous system tumors, with the identification of new recurrent somatic gain-of-function mutations, occurring in 0.8% of glioblastomaIDH-wildtype.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
