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

Monteagudo, Maria; Martinez, Paula; Leandro-Garcia, Luis J.; Martinez-Montes, Angel M.; Calsina, Bruna; Pulgarin-Alfaro, Marta; Diaz-Talavera, Alberto; Mellid, Sara; Leton, Rocio; Gil, Eduardo; Perez-Martinez, Manuel; Megias, Diego; Torres-Ruiz, Raul; Rodriguez-Perales, Sandra; Gonzalez, Patricia; Caleiras, Eduardo; Jimenez-Villa, Scherezade; Roncador, Giovanna; Alvarez-Escola, Cristina; Regojo, Rita M.; Calatayud, Maria; Guadalix, Sonsoles; Curras-Freixes, Maria; Rapizzi, Elena; Canu, Letizia; Noelting, Svenja; Remde, Hanna; Fassnacht, Martin; Bechmann, Nicole; Eisenhofer, Graeme; Mannelli, Massimo; Beuschlein, Felix; Quinkler, Marcus; Rodriguez-Antona, Cristina; Cascon, Alberto; Blasco, Maria A.; Montero-Conde, Cristina und Robledo, Mercedes (2021): Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma. In: Cancers, Bd. 13, Nr. 19, 4758

Abstract

Simple Summary:& nbsp;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.</p> <br></p> 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.</p>

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch