Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma
by
, , , , , , , , , , , and
María Monteagudo
1,2,†
,
Paula Martínez
3,†,
Luis J. Leandro-García
1,
Ángel M. Martínez-Montes
1,
Bruna Calsina
1,
Marta Pulgarín-Alfaro
1,
Alberto Díaz-Talavera
1,4
,
Sara Mellid
1,
Rocío Letón
1,
Eduardo Gil
1,
Manuel Pérez-Martínez
5,
Diego Megías
5,
Raúl Torres-Ruiz
6,
Sandra Rodriguez-Perales
6,
Patricia González
7,
Eduardo Caleiras
7,
Scherezade Jiménez-Villa
8,
Giovanna Roncador
8,
Cristina Álvarez-Escolá
9,
Rita M. Regojo
10,
María Calatayud
11,
Sonsoles Guadalix
11,
Maria Currás-Freixes
12,
Elena Rapizzi
13
,
Letizia Canu
13
,
Svenja Nölting
14,
Hanna Remde
15,
Martin Fassnacht
15,16,
Nicole Bechmann
17,18,
Graeme Eisenhofer
17,18,
Massimo Mannelli
13,
Felix Beuschlein
14,19,
Marcus Quinkler
20,
Cristina Rodríguez-Antona
1,4, 
Alberto Cascón
1,4
,
María A. Blasco
3,
Cristina Montero-Conde
1,4 and
Mercedes Robledo
1,4,*add
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1
Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
2
PhD Program in Neuroscience, Autonoma de Madrid University, 28029 Madrid, Spain
3
Telomeres and telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
4
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
5
Confocal Microscopy Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
6
Molecular Citogenetic, Unit Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
7
Histopathology Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
8
Monoclonal Antibodies Core Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
9
Department of Endocrinology, La Paz University Hospital, 28046 Madrid, Spain
10
Department of Pathology La Paz University Hospital, 28046 Madrid, Spain
11
Department of Endocrinology, 12 de Octubre University Hospital, 28041 Madrid, Spain
12
Department of Endocrinology, Clínica Universidad de Navarra, 28027 Madrid, Spain
13
Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
14
Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
15
Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, 97070 Würzburg, Germany
16
Comprehensive Cancer Center, Mainfranken University of Würzburg, 97070 Würzburg, Germany
17
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01069 Dresden, Germany
18
Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01069 Dresden, Germany
19
Klinik für Endokrinologie Diabetologie und Klinische Ernährung, Universitätsspital Zürich, 8091 Zürich, Switzerland
20
Endocrinology in Charlottenburg Stuttgarter Platz 1, 10627 Berlin, Germany
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2021, 13(19), 4758; https://doi.org/10.3390/cancers13194758
Submission received: 26 August 2021
/
Revised: 17 September 2021
/
Accepted: 19 September 2021
/
Published: 23 September 2021
(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)
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.
Keywords:
pheochromocytoma; paraganglioma; PPGL; telomeres; TERT; ATRX; NOP10; prognostic biomarker; ALT
