Succinate: A Serum Biomarker of SDHB-Mutated Paragangliomas and Pheochromocytomas

Context: Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that are frequently associated with succinate dehydrogenase (SDH) germline mutations. When mutated, SDH losses its function, thus leading to succinate accumulation. Objective: In this study, we evaluated serum succinate levels as a new metabolic biomarker in SDHx-related carriers. Methods: Retrospective monocentric study of 88 PPGL patients (43 sporadic, 35 SDHB, 10 SDHA/C/D), 17 tumor-free familial asymptomatic carriers (13 SDHB, 4 SDHC/D), and 60 healthy controls. Clinical, biological, and imaging data were reviewed. Serum succinate levels (n=280) were quantified by an ultra-performance liquid chromatography coupled to a tandem mass spectrometry method and correlated to SDHx mutational status, disease extension, and other biological biomarkers. Results: Serum succinate levels>7 μM allowed identification of tumor-free asymptomatic SDHB-mutated cases compared to a healthy control group (100% specificity; 85% sensitivity). At PPGL diagnosis, SDHB-mutated patients had a significantly increased median succinate level (14 μM) compared to sporadic patients (8 μM) (P<0.01). Metastatic disease extension was correlated to serum succinate levels (r=0.81). In the SDHB group, patients displaying highest tumor burdens showed significant increased succinate levels compared to the sporadic group (P<0.0001). Conclusions: In this pilot study, we showed that serum succinate level is an oncometabolic biomarker that should be useful to identify SDHB-related carriers. Succinate levels are also a marker of metabolic tumor burden in patients with a metastatic PPGL and a potential marker of treatment response and follow-up.