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Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma

SIMPLE SUMMARY: Telomere maintenance involving TERT and ATRX genes has been recently described in metastatic pheochromocytoma and paraganglioma, reinforcing the importance of immortalization mechanisms in the progression of these tumors. Thus, the aim of this study was to analyze additional telomere...

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Autores principales: Monteagudo, María, Martínez, Paula, Leandro-García, Luis J., Martínez-Montes, Ángel M., Calsina, Bruna, Pulgarín-Alfaro, Marta, Díaz-Talavera, Alberto, Mellid, Sara, Letón, Rocío, Gil, Eduardo, Pérez-Martínez, Manuel, Megías, Diego, Torres-Ruiz, Raúl, Rodriguez-Perales, Sandra, González, Patricia, Caleiras, Eduardo, Jiménez-Villa, Scherezade, Roncador, Giovanna, Álvarez-Escolá, Cristina, Regojo, Rita M., Calatayud, María, Guadalix, Sonsoles, Currás-Freixes, Maria, Rapizzi, Elena, Canu, Letizia, Nölting, Svenja, Remde, Hanna, Fassnacht, Martin, Bechmann, Nicole, Eisenhofer, Graeme, Mannelli, Massimo, Beuschlein, Felix, Quinkler, Marcus, Rodríguez-Antona, Cristina, Cascón, Alberto, Blasco, María A., Montero-Conde, Cristina, Robledo, Mercedes
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507560/
https://www.ncbi.nlm.nih.gov/pubmed/34638246
http://dx.doi.org/10.3390/cancers13194758
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author Monteagudo, María
Martínez, Paula
Leandro-García, Luis J.
Martínez-Montes, Ángel M.
Calsina, Bruna
Pulgarín-Alfaro, Marta
Díaz-Talavera, Alberto
Mellid, Sara
Letón, Rocío
Gil, Eduardo
Pérez-Martínez, Manuel
Megías, Diego
Torres-Ruiz, Raúl
Rodriguez-Perales, Sandra
González, Patricia
Caleiras, Eduardo
Jiménez-Villa, Scherezade
Roncador, Giovanna
Álvarez-Escolá, Cristina
Regojo, Rita M.
Calatayud, María
Guadalix, Sonsoles
Currás-Freixes, Maria
Rapizzi, Elena
Canu, Letizia
Nölting, Svenja
Remde, Hanna
Fassnacht, Martin
Bechmann, Nicole
Eisenhofer, Graeme
Mannelli, Massimo
Beuschlein, Felix
Quinkler, Marcus
Rodríguez-Antona, Cristina
Cascón, Alberto
Blasco, María A.
Montero-Conde, Cristina
Robledo, Mercedes
author_facet Monteagudo, María
Martínez, Paula
Leandro-García, Luis J.
Martínez-Montes, Ángel M.
Calsina, Bruna
Pulgarín-Alfaro, Marta
Díaz-Talavera, Alberto
Mellid, Sara
Letón, Rocío
Gil, Eduardo
Pérez-Martínez, Manuel
Megías, Diego
Torres-Ruiz, Raúl
Rodriguez-Perales, Sandra
González, Patricia
Caleiras, Eduardo
Jiménez-Villa, Scherezade
Roncador, Giovanna
Álvarez-Escolá, Cristina
Regojo, Rita M.
Calatayud, María
Guadalix, Sonsoles
Currás-Freixes, Maria
Rapizzi, Elena
Canu, Letizia
Nölting, Svenja
Remde, Hanna
Fassnacht, Martin
Bechmann, Nicole
Eisenhofer, Graeme
Mannelli, Massimo
Beuschlein, Felix
Quinkler, Marcus
Rodríguez-Antona, Cristina
Cascón, Alberto
Blasco, María A.
Montero-Conde, Cristina
Robledo, Mercedes
author_sort Monteagudo, María
collection PubMed
description SIMPLE SUMMARY: Telomere maintenance involving TERT and ATRX genes has been recently described in metastatic pheochromocytoma and paraganglioma, reinforcing the importance of immortalization mechanisms in the progression of these tumors. Thus, the aim of this study was to analyze additional telomere-related genes to uncover potential new markers capable of identifying metastatic-risk patients more accurately. After analyzing 29 telomere-related genes, we were able to validate the predictive value of TERT and ATRX in mPPGL progression. In addition, we were able to identify NOP10 as a novel prognostic risk marker of mPPGLs, which also facilitates telomerase-dependent telomere length maintenance in these tumors. Interestingly, NOP10 overexpression assessment by IHC could be easily included within the current battery of markers for stratifying PPGL patients to fine-tune their clinical diagnoses. ABSTRACT: One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients.
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spelling pubmed-85075602021-10-13 Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma Monteagudo, María Martínez, Paula Leandro-García, Luis J. Martínez-Montes, Ángel M. Calsina, Bruna Pulgarín-Alfaro, Marta Díaz-Talavera, Alberto Mellid, Sara Letón, Rocío Gil, Eduardo Pérez-Martínez, Manuel Megías, Diego Torres-Ruiz, Raúl Rodriguez-Perales, Sandra González, Patricia Caleiras, Eduardo Jiménez-Villa, Scherezade Roncador, Giovanna Álvarez-Escolá, Cristina Regojo, Rita M. Calatayud, María Guadalix, Sonsoles Currás-Freixes, Maria Rapizzi, Elena Canu, Letizia Nölting, Svenja Remde, Hanna Fassnacht, Martin Bechmann, Nicole Eisenhofer, Graeme Mannelli, Massimo Beuschlein, Felix Quinkler, Marcus Rodríguez-Antona, Cristina Cascón, Alberto Blasco, María A. Montero-Conde, Cristina Robledo, Mercedes Cancers (Basel) Article SIMPLE SUMMARY: Telomere maintenance involving TERT and ATRX genes has been recently described in metastatic pheochromocytoma and paraganglioma, reinforcing the importance of immortalization mechanisms in the progression of these tumors. Thus, the aim of this study was to analyze additional telomere-related genes to uncover potential new markers capable of identifying metastatic-risk patients more accurately. After analyzing 29 telomere-related genes, we were able to validate the predictive value of TERT and ATRX in mPPGL progression. In addition, we were able to identify NOP10 as a novel prognostic risk marker of mPPGLs, which also facilitates telomerase-dependent telomere length maintenance in these tumors. Interestingly, NOP10 overexpression assessment by IHC could be easily included within the current battery of markers for stratifying PPGL patients to fine-tune their clinical diagnoses. ABSTRACT: One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients. MDPI 2021-09-23 /pmc/articles/PMC8507560/ /pubmed/34638246 http://dx.doi.org/10.3390/cancers13194758 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Monteagudo, María
Martínez, Paula
Leandro-García, Luis J.
Martínez-Montes, Ángel M.
Calsina, Bruna
Pulgarín-Alfaro, Marta
Díaz-Talavera, Alberto
Mellid, Sara
Letón, Rocío
Gil, Eduardo
Pérez-Martínez, Manuel
Megías, Diego
Torres-Ruiz, Raúl
Rodriguez-Perales, Sandra
González, Patricia
Caleiras, Eduardo
Jiménez-Villa, Scherezade
Roncador, Giovanna
Álvarez-Escolá, Cristina
Regojo, Rita M.
Calatayud, María
Guadalix, Sonsoles
Currás-Freixes, Maria
Rapizzi, Elena
Canu, Letizia
Nölting, Svenja
Remde, Hanna
Fassnacht, Martin
Bechmann, Nicole
Eisenhofer, Graeme
Mannelli, Massimo
Beuschlein, Felix
Quinkler, Marcus
Rodríguez-Antona, Cristina
Cascón, Alberto
Blasco, María A.
Montero-Conde, Cristina
Robledo, Mercedes
Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma
title Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma
title_full Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma
title_fullStr Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma
title_full_unstemmed Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma
title_short Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma
title_sort analysis of telomere maintenance related genes reveals nop10 as a new metastatic-risk marker in pheochromocytoma/paraganglioma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507560/
https://www.ncbi.nlm.nih.gov/pubmed/34638246
http://dx.doi.org/10.3390/cancers13194758
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