Biomarkers Improving Genetic and Metastatic Disease Prediction in Paraganglioma: Insights From a Prospective Study
Authors: Drossart Tom , Buffet Alexandre , Janbain Ali , Ottolenghi Chris , Amar Laurence , Libé Rossella , Drui Delphine , Lussey-Lepoutre Charlotte , Mancini Maxence , Lounis Timgad , Guénégou-Arnoux Armelle , Méatchi Tchao , Bertherat Jérôme , Burnichon Nelly , Favier Judith , Gimenez-Roqueplo Anne-Paule ,   COMETE-TACTIC Study Group, Gimenez-Roqueplo Anne-Paule , Amar Laurence , Manceau Gilles , Madjalian Anne-Marie , Faucon Anne-Laure , Cornu Erika , Laboureau-Soares Sandrine , Allix Ingrid , Illouz Frédéric , Lalmi Fairouz , Gauthier Aline , Sekour Belaïd , Lefebvre Hervé , Cailleux Anne-Françoise , Le Bolc'h Romain , Berrahmoune Hind , Sonnet Emmanuel , Doucet Laurent , Joulin Vincent , Borson-Chazot Françoise , Lasolle Hélène , Lifante Jean-Christophe , Maillard Laure , Decaussin-Petrucci Myriam , Delahaye Armelle , Batisse-Lignier Marie , Bouvier Damien , Godfraind Catherine , Chabre Olivier , Chaffanjon Philippe , Sturm Nathalie , Schummer Gabriel , Cristante Justine , Nasse Laure , Fassio Flora , Raingeard Isabelle , Gall Emmanuelle , Zerkowski Laetitia , Dupuy Anne Marie , Llorcy Frédérique , Drui Delphine , Le Bras Maëlle , Fournier Anne-Laure , Landau Ester , Barrak Elias , Cariou Bertrand , Dierry Violette , Ernould Audrey , Mirallié Eric , Caillard Cécile , Ferron Christophe , Renaudin Karine , Girard Cécile , Bertherat Jérôme , Guignat Laurence , Groussin Lionel , Assié Guillaume , Libé Rossella , Jouinot Anne , Saidi Meriama , Perlemoine Karine , Sibony Mathilde , Terris Benoit , Parfait Béatrice , Lussey-Lepoutre Charlotte , Laroche Suzanne , Jublanc Christel , Grouthier Virginie , Tresallet Christophe , Menegaux Pr Fabrice , Deniziaut Gabrielle , Herve Genevieve , Brocheriou Isabelle , Delattre Jean-Yves , Detrait Ines , Tabarin Antoine , Haissaguerre Magalie , Galioot Amandine , Puerto Marie , Guilhem Isabelle , Guenego Agathe , Esvant Annabelle , Manunta Andréa , Goichot Bernard , Vix Michel , Mutter Didier , Lang Hervé , Addeo Pietro , Pierre Peggy Renoult , Crinière Lise , Guyétant Serge , Fromont Gaëlle , Bruyére Franck , d'Arcier Benjamin Faivre , Bourbao Céline , Baudin Eric , Leboulleux Sophie , Hadoux Julien , Lamartina Livia 
Published: November 2024

Abstract

Context and Objective
Identifying the risk of malignancy and genetic status in primary paraganglioma or pheochromocytoma (PPGL) is a key challenge. The aim was to assess the diagnostic accuracy of genomic, metabolomic and histopathological biomarkers for predicting metastatic and genetic status.

Design, Setting, and Patients
COMETE-TACTIC is a prospective study (NCT02672020) conducted from November 2015 to March 2019 across 16 referral centers. Tumor samples and liquid biopsies from 231 consecutive patients with PPGL were collected.

Main Outcome Measures
Germline and somatic genetic status were determined by next-generation sequencing, SDHB, SDHA and CA9 immunohistochemistries were performed on tumor tissues. TERT promoter methylation was assessed by pyrosequencing. Metabolomic profile and circulating miRNAs were measured in liquid biopsies by gas chromatography MS/MS and TaqMan assay quantified by droplet digital PCR, respectively.

Results
Tumor analysis outperformed germline analysis for determining genetic status. Positive SDHA and SDHB staining combined with negative CA9 labeling indicated the absence of SDHx and VHL variants. Plasma succinate levels above 4.94 µM identified SDHx mutation carriers with 65% sensitivity and 92% specificity [area under the receiver operating characteristic curve (AUC-ROC) 0.82, 95% confidence interval (CI) 0.70-0.93]. Among circulating miRNAs, miR-483-5p was the best classifier of metastatic status (AUC-ROC 0.64, 95%CI 0.52-0.77). A sum of dinucleotide methylation rate of TERT promoter CpGs above 42% predicted metastatic status (AUC-ROC 0.75, 95% CI 0.65-0.85). Multivariate analyses showed that biomarker combinations significantly predicted SDHx status (AUC-ROC 0.99, 95% CI 0.98-1.00) and metastatic potential (AUC-ROC 0.93, 95% CI 0.84-1).

Conclusion
Circulating miR-483-5p, plasma succinate, TERT promoter methylation, and SDHB immunostaining are valuable for PPGL risk stratification. Combining biomarkers with clinical data provides excellent diagnostic accuracy for metastatic patients (AUC-ROC 0.97, 95%CI 0.93-1).