Utility of the succinate:fumarate ratio for assessing SDH dysfunction in different tumor types

Kim, Edward; Wright, Michael J.; Sioson, Loretta; Novos, Talia; Gill, Anthony J.; Benn, Diana E.; White, Curt M.; Dwight, Trisha; Clifton‐Bligh, Roderick

doi:10.1016/j.ymgmr.2016.12.006

Cited by 25 publications

(29 citation statements)

References 30 publications

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“…This score combines pathological features with biochemical phenotypes but does not include the SDHB mutational status of the tumor. Therefore, a Tumor tissue can be used to measure the succinate:fumarate ratio using liquid chromatography-mass spectrometry (LC-MS) 112,113. An elevated succinate:fumarate ratio provides a diagnostic sensitivity of 93% and sensitivity of 97% to identify SDHx mutated PGL/PCC 87.…”

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confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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Succinate dehydrogenase (SDH) mutations lead to the accumulation of succinate, which acts as an oncometabolite. Germline SDHx mutations predispose to paraganglioma (PGL) and pheochromocytoma (PCC), as well as to renal cell carcinoma and gastro-intestinal stromal tumors. The SDHx genes were the first tumor suppressor genes discovered which encode for a mitochondrial enzyme, thereby supporting Otto Warburg's hypothesis in 1926 that a direct link existed between mitochondrial dysfunction and cancer. Accumulation of succinate is the hallmark of tumorigenesis in PGL and PCC. Succinate accumulation inhibits several α-ketoglutarate dioxygenases, thereby inducing the pseudohypoxia pathway and causing epigenetic changes. Moreover, SDH loss as a consequence of SDHx mutations can lead to reprogramming of cell metabolism. Metabolomics can be used as a diagnostic tool, as succinate and other metabolites can be measured in tumor tissue, plasma and urine with different techniques. Furthermore, these pathophysiological characteristics provide insight into therapeutic targets for metastatic disease. This review provides an overview of the pathophysiology and clinical implications of oncometabolite succinate in SDHx mutations. K E Y W O R D S oncometabolites, paraganglioma, pheochromocytoma, SDH mutation, succinate 1 | INTRODUCTION Mutations of genes encoding for the succinate dehydrogenase (SDH) complex, associated with familial paraganglioma (PGL) and pheochromocytoma (PCC), lead to accumulation of succinate, which disturbs the metabolic regulation of the cell. Nowadays metabolic dysregulation is recognized as one of the eight hallmarks of cancer. 1 Although germline mutations in SDHx genes are predominantly linked to PGL and PCC, these mutations also predispose to renal cell carcinoma (RCC), gastrointestinal stromal tumors (GISTs) and, possibly, pituitary adenomas. PCC, PGL and head and neck PGL (HNPGL) are rare neuroendocrine tumors arising from chromaffin cells that can synthesize and release catecholamines. Sympathetic PGLs are derived from sympathetic paraganglia in the chest, abdomen or pelvis. PCC are PGLs located in the adrenal medulla. 2 HNPGLs are derived from parasympathetic paraganglia. Common locations for HNPGLs include the carotid body and the middle ear, as well as the vagus nerve and internal jugular vein. While parasympathetic PGLs are most often non-functional tumors, PCC and sympathetic PGL release catecholamines into the circulation and can

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confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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“…Kim et al [44] reported metabolomic results for a smaller series of 18 PPGLs (9 SDHx-related), measuring only succinate and fumarate in FFPE samples and confirming a higher succinate:fumarate ratio in SDHx-associated PPGLs, with a similar cut-off (67.1) to Richter et al [41] albeit with a high false-negative rate (5/9, 56 %). VHL-associated PPGLs demonstrated high-normal succinate:fumarate ratios, due to lower fumarate levels previously noted by [41].…”

Section: Mass Spectrometry In Metabolomic Assessment Of Ppglsmentioning

confidence: 78%

“…The diagnostic significance of metabolomics thus far has been: (a) to validate enzymatic defects in PPGLs associated with specific genetic variants [13,22,23,41,44,45]; and (b) as a discovery tool to diagnose previously unrecognized phenomena associated with PPGL, for example, somatic SDHx or IDH2 variants [45], or epigenetic defects as a mechanism for SDH deficiency (SDHC promoter hypermethylation) [42]. For the former application, the utility of LC-MS/MS can be compared against immunohistochemistry (IHC) now successfully developed for SDHB (IHC for which is lost in any SDHx-related tumor) [55,56], SDHA (specific for SDHA-associated tumor) [57] and FH (lost in FH-related tumors) [45].…”

Section: Discussionmentioning

confidence: 99%

Metabolomics in the Diagnosis of Pheochromocytoma and Paraganglioma

Dwight

Kim

Novos³

et al. 2019

Horm Metab Res

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Metabolomics refers to the detection and measurement of small molecules (metabolites) within biological systems, and is therefore a powerful tool for identifying dysfunctional cellular physiologies. For pheochromocytomas and paragangliomas (PPGLs), metabolomics has the potential to become a routine addition to histology and genomics for precise diagnostic evaluation. Initial metabolomic studies of ex vivo tumors confirmed, as expected, succinate accumulation in PPGLs associated with pathogenic variants in genes encoding succinate dehydrogenase subunits or their assembly factors (SDHx). Metabolomics has now shown utility in clarifying SDHx variants of uncertain significance, as well as the accurate diagnosis of PPGLs associated with fumarate hydratase (FH), isocitrate dehydrogenase (IDH), malate dehydrogenase (MDH2) and aspartate transaminase (GOT2). The emergence of metabolomics resembles the advent of genetic testing in this field, which began with single-gene discoveries in research laboratories but is now done by standardized massively parallel sequencing (targeted panel/exome/genome testing) in pathology laboratories governed by strict credentialing and governance requirements. In this setting, metabolomics is poised for rapid translation as it can utilize existing infrastructure, namely liquid chromatography-tandem mass spectrometry (LC-MS/MS), for the measurement of catecholamine metabolites. Metabolomics has also proven tractable to in vivo diagnosis of SDH-deficient PPGLs using magnetic resonance spectroscopy (MRS). The future of metabolomics – embedded as a diagnostic tool – will require adoption by pathologists to shepherd development of standardized assays and sample preparation, reference ranges, gold standards, and credentialing.

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“…In other words, absence of SDHA staining is specifically associated with SDHA mutations. 12,14 Furthermore, elevated succinate to fumarate ratio is a consistent biomolecular phenotype of SDH-deficient tumors as demonstrated by Kim et al 15 using mass spectrometry to quantitatively analyze SDH dysfunction. Therefore, germline mutations in SDH as well as hypermethylation of the SDHC promoter can result in an elevated succinate to fumarate ratio, extending support to the above-described pseudohypoxia mechanism.…”

Section: Physiologymentioning

confidence: 91%

“…Therefore, germline mutations in SDH as well as hypermethylation of the SDHC promoter can result in an elevated succinate to fumarate ratio, extending support to the above-described pseudohypoxia mechanism. 15 Syndromic Associations SCD syndrome, also known as hereditary paraganglioma/ pheochromocytoma syndrome or familial paraganglioma syndrome, is caused by germline loss-of-function mutations in SDH and SDHAF2. 3 Their syndromic associations with multiple tumors have only recently come to light, resulting in their segregation based on the underlying gene and the corresponding phenotypic correlation into 5 types that demonstrate unique clinical characteristics such as tumor site, multiplicity, function, risk of recurrence, and metastasis.…”

Section: Physiologymentioning

confidence: 99%

Succinate Dehydrogenase Complex: An Updated Review

Rasheed

Tarján

2018

Archives of Pathology &Amp; Laboratory Medicine

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Succinate dehydrogenase (SDH) is uniquely tasked with a dual role in the essential energy-producing processes of a cell. Although SDH subunits and assembly factors form part of the same enzyme complex, mutations in their respective genes lead to significantly different clinical phenotypes. Remarkable discoveries in the last 17 years have led to the delineation of the SDH complex deficiency syndrome and its multiple pathogenic branches. Here we provide an updated overview of SDH deficiency in order to raise awareness of its multiple connotations including nonneoplastic associations and pertinent features of the continually growing list of SDH-mutant tumors so as to better direct genetic counseling and predict prognosis.

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Utility of the succinate:fumarate ratio for assessing SDH dysfunction in different tumor types

Cited by 25 publications

References 30 publications

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Metabolomics in the Diagnosis of Pheochromocytoma and Paraganglioma

Succinate Dehydrogenase Complex: An Updated Review

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