TY  - JOUR
A1  - Monteagudo, María
A1  - Martínez, Paula
A1  - Leandro-García, Luis J.
A1  - Martínez-Montes, Ángel M.
A1  - Calsina, Bruna
A1  - Pulgarín-Alfaro, Marta
A1  - Díaz-Talavera, Alberto
A1  - Mellid, Sara
A1  - Letón, Rocío
A1  - Gil, Eduardo
A1  - Pérez-Martínez, Manuel
A1  - Megías, Diego
A1  - Torres-Ruiz, Raúl
A1  - Rodriguez-Perales, Sandra
A1  - González, Patricia
A1  - Caleiras, Eduardo
A1  - Jiménez-Villa, Scherezade
A1  - Roncador, Giovanna
A1  - Álvarez-Escolá, Cristina
A1  - Regojo, Rita M.
A1  - Calatayud, María
A1  - Guadalix, Sonsoles
A1  - Currás-Freixes, Maria
A1  - Rapizzi, Elena
A1  - Canu, Letizia
A1  - Nölting, Svenja
A1  - Remde, Hanna
A1  - Fassnacht, Martin
A1  - Bechmann, Nicole
A1  - Eisenhofer, Graeme
A1  - Mannelli, Massimo
A1  - Beuschlein, Felix
A1  - Quinkler, Marcus
A1  - Rodríguez-Antona, Cristina
A1  - Cascón, Alberto
A1  - Blasco, María A.
A1  - Montero-Conde, Cristina
A1  - Robledo, Mercedes
T1  - Analysis of telomere maintenance related genes reveals NOP10 as a new metastatic-risk marker in pheochromocytoma/paraganglioma
JF  - Cancers
N2  - 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.
KW  - pheochromocytoma
KW  - paraganglioma
KW  - PPGL
KW  - telomeres
KW  - prognostic biomarker
KW  - ALT
KW  - TERT
KW  - ATRX
KW  - NOP10
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246321
SN  - 2072-6694
VL  - 13
IS  - 19
ER  - 
TY  - JOUR
A1  - März, Juliane
A1  - Kurlbaum, Max
A1  - Roche-Lancaster, Oisin
A1  - Deutschbein, Timo
A1  - Peitzsch, Mirko
A1  - Prehn, Cornelia
A1  - Weismann, Dirk
A1  - Robledo, Mercedes
A1  - Adamski, Jerzy
A1  - Fassnacht, Martin
A1  - Kunz, Meik
A1  - Kroiss, Matthias
T1  - Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors
JF  - Frontiers in Endocrinology
N2  - Context
Pheochromocytomas and paragangliomas (PPGL) cause catecholamine excess leading to a characteristic clinical phenotype. Intra-individual changes at metabolome level have been described after surgical PPGL removal. The value of metabolomics for the diagnosis of PPGL has not been studied yet.

Objective
Evaluation of quantitative metabolomics as a diagnostic tool for PPGL.

Design
Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens and statistical modeling using ML-based feature selection approaches in a clinically well characterized cohort study.

Patients
Prospectively enrolled patients (n=36, 17 female) from the Prospective Monoamine-producing Tumor Study (PMT) with hormonally active PPGL and 36 matched controls in whom PPGL was rigorously excluded.

Results
Among 188 measured metabolites, only without considering false discovery rate, 4 exhibited statistically significant differences between patients with PPGL and controls (histidine p=0.004, threonine p=0.008, lyso PC a C28:0 p=0.044, sum of hexoses p=0.018). Weak, but significant correlations for histidine, threonine and lyso PC a C28:0 with total urine catecholamine levels were identified. Only the sum of hexoses (reflecting glucose) showed significant correlations with plasma metanephrines.
By using ML-based feature selection approaches, we identified diagnostic signatures which all exhibited low accuracy and sensitivity. The best predictive value (sensitivity 87.5%, accuracy 67.3%) was obtained by using Gradient Boosting Machine Modelling.

Conclusions
The diabetogenic effect of catecholamine excess dominates the plasma metabolome in PPGL patients. While curative surgery for PPGL led to normalization of catecholamine-induced alterations of metabolomics in individual patients, plasma metabolomics are not useful for diagnostic purposes, most likely due to inter-individual variability.
KW  - adrenal
KW  - pheochromocytoma
KW  - paraganglioma
KW  - targeted metabolomics
KW  - mass spectronomy
KW  - catecholamines
KW  - machine learning
KW  - feature selection
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245710
SN  - 1664-2392
VL  - 12
ER  -