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New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma

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 pro...

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Autores principales: Pierini, Tiziana, Nardelli, Carlotta, Lema Fernandez, Anair Graciela, Pierini, Valentina, Pellanera, Fabrizia, Nofrini, Valeria, Gorello, Paolo, Moretti, Martina, Arniani, Silvia, Roti, Giovanni, Giovenali, Paolo, Lupattelli, Marco, Metro, Giulio, Molica, Carmen, Castrioto, Corrado, Corinaldesi, Rodolfo, Laurenti, Maria Elena, Ascani, Stefano, Mecucci, Cristina, La Starza, Roberta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445914/
https://www.ncbi.nlm.nih.gov/pubmed/32843091
http://dx.doi.org/10.1186/s40478-020-01022-4
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author Pierini, Tiziana
Nardelli, Carlotta
Lema Fernandez, Anair Graciela
Pierini, Valentina
Pellanera, Fabrizia
Nofrini, Valeria
Gorello, Paolo
Moretti, Martina
Arniani, Silvia
Roti, Giovanni
Giovenali, Paolo
Lupattelli, Marco
Metro, Giulio
Molica, Carmen
Castrioto, Corrado
Corinaldesi, Rodolfo
Laurenti, Maria Elena
Ascani, Stefano
Mecucci, Cristina
La Starza, Roberta
author_facet Pierini, Tiziana
Nardelli, Carlotta
Lema Fernandez, Anair Graciela
Pierini, Valentina
Pellanera, Fabrizia
Nofrini, Valeria
Gorello, Paolo
Moretti, Martina
Arniani, Silvia
Roti, Giovanni
Giovenali, Paolo
Lupattelli, Marco
Metro, Giulio
Molica, Carmen
Castrioto, Corrado
Corinaldesi, Rodolfo
Laurenti, Maria Elena
Ascani, Stefano
Mecucci, Cristina
La Starza, Roberta
author_sort Pierini, Tiziana
collection PubMed
description 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 (TERTp(mut)) 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 (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/Krüppel-Like Factor groups. In fact, these new TERTp(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 TERTp(mut). On the other hand, they were distinguished by enhanced affinity for the Krüppel proteins. The luciferase assay confirmed that TERTp(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 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-020-01022-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-74459142020-08-26 New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma Pierini, Tiziana Nardelli, Carlotta Lema Fernandez, Anair Graciela Pierini, Valentina Pellanera, Fabrizia Nofrini, Valeria Gorello, Paolo Moretti, Martina Arniani, Silvia Roti, Giovanni Giovenali, Paolo Lupattelli, Marco Metro, Giulio Molica, Carmen Castrioto, Corrado Corinaldesi, Rodolfo Laurenti, Maria Elena Ascani, Stefano Mecucci, Cristina La Starza, Roberta Acta Neuropathol Commun Case Report 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 (TERTp(mut)) 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 (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/Krüppel-Like Factor groups. In fact, these new TERTp(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 TERTp(mut). On the other hand, they were distinguished by enhanced affinity for the Krüppel proteins. The luciferase assay confirmed that TERTp(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 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-020-01022-4) contains supplementary material, which is available to authorized users. BioMed Central 2020-08-25 /pmc/articles/PMC7445914/ /pubmed/32843091 http://dx.doi.org/10.1186/s40478-020-01022-4 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Case Report
Pierini, Tiziana
Nardelli, Carlotta
Lema Fernandez, Anair Graciela
Pierini, Valentina
Pellanera, Fabrizia
Nofrini, Valeria
Gorello, Paolo
Moretti, Martina
Arniani, Silvia
Roti, Giovanni
Giovenali, Paolo
Lupattelli, Marco
Metro, Giulio
Molica, Carmen
Castrioto, Corrado
Corinaldesi, Rodolfo
Laurenti, Maria Elena
Ascani, Stefano
Mecucci, Cristina
La Starza, Roberta
New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma
title New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma
title_full New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma
title_fullStr New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma
title_full_unstemmed New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma
title_short New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma
title_sort new somatic tert promoter variants enhance the telomerase activity in glioblastoma
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445914/
https://www.ncbi.nlm.nih.gov/pubmed/32843091
http://dx.doi.org/10.1186/s40478-020-01022-4
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