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 mu M 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 mu M) compared to sporadic patients (8 mu M) (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.

Automated summary

In this study, serum succinate levels were found to be a potential biomarker for identifying carriers of SDHB gene mutations and a marker of metabolic tumor burden in patients with metastatic PPGL. It may also serve as a marker for treatment response and follow-up.