Novel Germline SUCLG2 Mutations in Patients With Pheochromocytoma and Paraganglioma

Abstract

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells that are frequently linked to mutations including those in Krebs cycle enzymes, particularly succinate dehydrogenase (SDH). Succinyl-CoA ligase (SUCL) catalyzes reversible conversion of succinyl-CoA to succinate providing the substrate for SDH. While mitochondrial diseases were documented for the mutations in SUCL subunits G1 and A2, the association of GDP/GTP-specific subunit SUCLG2 mutations with specific pathologies including cancer have not been reported. In our study, 352 patients with apparently sporadic PPGLs underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health. Additionally, human pheochromocytoma (hPheo1) cells were used for gene manipulation to produce SUCLG2 knock-out (KO). Tumor tissues and hPheo1 SUCLG2 KO cells were used for further analysis focusing on mechanism of germline variants effect on mitochondrial functions. We detected eight germline SUCLG2 mutations in 15 patients which represents 4.3% of the cohort. Germline variants together with LOH led to decreased levels of SDH subunit B resulting in aberrant respiration and accumulation of succinate, well recognized oncometabolite. Manipulation of SUCLG2 in hPheo1 cells confirmed decrease in SDHB leading to faulty assembly of mitochondrial complex II and alteration of its respiration and activity. In summary, our study identified an association between SUCLG2 and PPGL. Larger scale sequencing and uncovering additional cases bearing SUCLG2 variants will further clarify the relationship between SUCLG2 and SDHx, particularly SDHB, as well as their role in disease etiology.

SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma

“…Patient Samples: Fresh LUAD tissues and adjacent normal tissues were obtained from the First Affiliated Hospital of Nanchang University with approval from the Medical Research Ethics Committee of the First Affiliated Hospital of Nanchang University (2020) CDYFYYLK (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). All samples were collected with the patients' informed consent and frozen and preserved at −80 °C for subsequent experimental analysis.…”

Genetics of Pheochromocytomas and Paragangliomas Determine the Therapeutical Approach

“…Recently, SUCLG2 has been identified as a novel candidate gene in hereditary PPGL. In the work of Vanova et al 2021, SUCLG2-mutated PPGL tumors and SUCLG2-deficient chromaffin cells revealed the decrease in the level of the SDHB subunit of SDH, and faulty assembly of the complex II, resulting in aberrant respiration and elevated succinate accumulation [24].…”

The connection between tricarboxylic acid cycle enzyme mutations and pseudohypoxic signaling in pheochromocytoma and paraganglioma

“…Within the context of certain PPGLs, genetic perturbations affecting enzymes integral to the TCA cycle, such as SDH and FH, emerge as salient features (56). Since the initial discovery in 2000 of the correlation between SDHD germline mutations and familial paragangliomatosis, a growing compendium has cataloged mutations within at least twelve TCA cycle-related genes in the landscape of PPGLs (SDHB, SDH, SDHC, SDHD, SDHAF2, FH, IDH1, MDH2, SUCLG2, DLST, SLC25A11, and GOT2) (8,57,58). Among these, SDHx, FH, IDH1, and MDH2 have garnered relatively more attention, with mutations within SDHx and FH, in particular, emerging as pivotal drivers in the genesis and Regulation of HIFa (HIF-1a/HIF-2a) by the PHD/VHL Pathway and Impact of Tricarboxylic Acid Cycle Metabolic Mutations.…”