Germline SUCLG2 Variants in Patients With Pheochromocytoma and Paraganglioma

Abstract

Background Pheochromocytoma and paraganglioma (PPGL) are neuroendocrine tumors with frequent mutations in genes linked to the tricarboxylic acid cycle. However, no pathogenic variant has been found to date in succinyl-CoA ligase (SUCL), an enzyme that provides substrate for succinate dehydrogenase (SDH; mitochondrial complex II; CII), a known tumor suppressor in PPGL. Methods A cohort of 352 subjects with apparently sporadic PPGL underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health, including the SUCLG2 subunit of SUCL. Gene deletion, succinate levels, and protein levels were assessed in tumors where possible. To confirm the possible mechanism, we used a progenitor cell line, hPheo1, derived from a human pheochromocytoma, and ablated and re-expressed SUCLG2. Results We describe eight germline variants in the GTP-binding domain of SUCLG2 in 15 patients (15 of 352, 4.3%) with apparently sporadic PPGL. Analysis of SUCLG2-mutated tumors and SUCLG2-deficient hPheo1 cells revealed absence of SUCLG2 protein, decrease in the level of the SDHB subunit of CII and faulty assembly of the complex, resulting in aberrant respiration and elevated succinate accumulation. Conclusions Our study suggests SUCLG2 as a novel candidate gene in the genetic landscape of PPGL. Large-scale sequencing may uncover additional cases harboring SUCLG2 variants and provide more detailed information about their prevalence and penetrance.

Value of Immunohistochemical Expression of Apelin, Succinate Dehydrogenase B, Chromogranin B, Human Epidermal Growth Factor Receptor-2, Contactin 4, and Succinyl-CoA Synthetase Subunit Beta in Differentiating Metastatic From Non-Metastatic Pheochromocytoma and Paraganglioma

“…Eight germline variants in the GTP-binding domain of SUCLG2 were found in 15 patients with sporadic PPGLs. The SUCLG2 protein was absent in PPGLs with mutated SUCLG-2 and SUCLG2-deficient hPheo1 cells ( 28 ). We analyzed the expression of SUCLG2 in metastatic and non-metastatic PPGLs using IHC.…”

“…A total of 20% of PPGLs or more harbor mutations in genes related to the TCA cycle. Recently, eight germline variants in the GTP-binding domain of SUCLG2 were found in 15 patients with sporadic PPGLs, suggesting the potential role of SUCLG2 as a new candidate prognostic gene in PPGLs ( 28 ).…”

Model systems in SDHx-related pheochromocytoma/paraganglioma

“…Later, germline mutations in the assembly factor SDHAF2 were found [ 14 ]. It has recently been suggested that mutations in succinate ligase ( SUCLG2 ), which attaches CoA to succinate in the TCA cycle, may also be a germline risk gene [ 15 ]. It was striking that the risk genes coded for a fundamental metabolic enzyme, rather than the replication-controlling enzymes that might be expected in a neoplastic condition [ 16 ].…”

Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity

“…Tumors originating from the adrenal medulla are known as pheochromocytomas (PHEOs), while those arising from sympathetic or parasympathetic ganglia are known as paragangliomas (PGLs). The pathogenesis of PPGLs can be attributed to more than 20 well-identified susceptibility genes [1][2][3]. Based on mutations in fifteen of these genes and involved pathways, PPGLs are categorized into three clusters according to their molecular mechanisms: pseudohypoxia (Cluster 1), with mutations in SDHB, FH, VHL, EPAS1, EGLN, and several other genes of the TCA cycle or mitochondrial function; kinase signaling (Cluster 2), represented by mutated RET, NF1, TMEM127, HRAS, FGFR1, and MAX; and Wnt-altered (Cluster 3), represented by MALMP3 and CSDE [2][3][4].…”

“…The pathogenesis of PPGLs can be attributed to more than 20 well-identified susceptibility genes [1][2][3]. Based on mutations in fifteen of these genes and involved pathways, PPGLs are categorized into three clusters according to their molecular mechanisms: pseudohypoxia (Cluster 1), with mutations in SDHB, FH, VHL, EPAS1, EGLN, and several other genes of the TCA cycle or mitochondrial function; kinase signaling (Cluster 2), represented by mutated RET, NF1, TMEM127, HRAS, FGFR1, and MAX; and Wnt-altered (Cluster 3), represented by MALMP3 and CSDE [2][3][4]. Clusters 1 and 2 make up a majority of the susceptibility genes causing the most common hereditary PPGLs.…”