Plasma succinate identifies SDHx deficiency and correlates with tumor burden
The study reports a prospective plasma metabolomics analysis identifying succinate as a biomarker for early diagnosis of germline and somatic SDHx variants. Investigators found that circulating succinate levels reflected SDHx deficiency and correlated with tumor burden, with longitudinal sampling suggesting utility for disease surveillance. Murine models of Sdhb deficiency confirmed tissue-level succinate accumulation, although circulating plasma concentrations differed from the human cohort, indicating species-specific metabolic thresholds. These findings position plasma succinate as a potential non-invasive diagnostic and monitoring tool for SDHx-associated pheochromocytomas, paragangliomas, and related tumors.
The original study
Investigating the clinical utility of plasma succinate with insights from a Sdhb deficient murine model.
- Authors
- Cole Y, Abramovich I, Fernandez-Garcia J, Docquier F, MacFarlane J, Xu X, et al.
- Journal
- Endocrine-related cancer
- Type
- Journal Article
- PMID
- 42758527
Original abstract
The succinate dehydrogenase (SDH) enzyme composed of four subunits (A-D) has a key role in the Krebs cycle and oxidative phosphorylation. Germline pathogenic variants (GPV) in the genes encoding the four subunits of the succinate dehydrogenase (SDH) enzyme (SDHA/SDHB/SDHC/SDHD), collectively known as SDHx are recognized as a paradigm for the role of disordered metabolism in oncogenesis as GPVs in SDHx lead to a truncated citric acid cycle due to reduced or absent function of the SDH enzyme and accumulation of the oncometabolite succinate. GPVs in SDHx are the most common cause of hereditary PPGL and are associated with a higher risk of malignant PPGL and predispose to other tumors including renal cell carcinoma, gastrointestinal stromal tumors (GIST) and pituitary adenomas. Utilizing the linkage of SDHx to metabolic dysfunction, we performed prospective plasma metabolomics and identified succinate as a biomarker for early diagnosis of an underlying SDHx variant. Succinate reflected SDHx deficiency, in individuals with germline predisposition and a small number of patients with somatic SDHx deficiency, and succinate levels correlated with tumor burden. Longitudinal sampling of patients illustrated that serial succinate measurements might be used as a biomarker for disease surveillance. These findings were validated by tissue analysis in a mouse model of Sdhb deficiency, where elevated succinate was observed in adrenal glands. While circulating plasma levels did not mirror the human cohort, this discrepancy suggests specific cellular thresholds for succinate or SDHx deficiency in adrenal gland tissue and highlights species-specific metabolic regulation.