SDHB-related pheochromocytoma and paraganglioma penetrance and genotype–phenotype correlations

Jochmanová, Ivana; Wolf, Katherine I.; King, Kathryn S.; Nambuba, Joan; Wesley, Robert; Martucci, Victoria; Raygada, Margarita; Adams, Karen T.; Prodanov, Tamara; Fojo, Antonio Tito; Lazúrová, Ivica; Pacák, Karel

doi:10.1007/s00432-017-2397-3

Cited by 71 publications

(76 citation statements)

References 43 publications

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“…In their retrospective cohort analysis (index and non‐index patients) the penetrance was 24% at age 60 years . Males seem to be slightly more at risk than females of developing a PGL …”

Section: Phenotype Of Sdhx Mutation Carriersmentioning

confidence: 98%

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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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“…In their retrospective cohort analysis (index and non‐index patients) the penetrance was 24% at age 60 years . Males seem to be slightly more at risk than females of developing a PGL …”

Section: Phenotype Of Sdhx Mutation Carriersmentioning

confidence: 98%

“…40 Males seem to be slightly more at risk than females of developing a PGL. 40,41 SDHB-related PGL/PCC are associated with a high risk of metastasis and poor prognosis. Earlier studies report a higher metastatic rate (31%-97%) [42][43][44][45] than more recent studies.…”

Section: Sdhb Mutationsmentioning

confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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“…The importance of surveillance screening in asymptomatic relatives is highlighted when analysing studies that separate out the asymptomatic carriers/relatives from the index cases (Table ). These combined cohorts provide data on 1341 asymptomatic SDHB carriers and demonstrate a tumour detection rate of 15.4% (207 asymptomatic carriers with PPGLs identified on screening), when index cases are excluded (individual studies report a tumour detection rate ranging from 3.5% to 35%) . Penetrance estimates have fallen over time as more disease‐free asymptomatic carriers are identified.…”

Section: Surveillance Programmesmentioning

confidence: 99%

Can subunit‐specific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?

Tufton

Sahdev

Drake

et al. 2018

Clinical Endocrinology

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Objective: With the discovery that familial phaeochromocytoma and paraganglioma syndrome can be caused by mutations in each subunit of the succinate dehydrogenase enzyme (SDH), has come the recognition that mutations in the individual subunits have their own distinct natural histories. Increased genetic screening is leading to the identification of increasing numbers of, mostly asymptomatic, gene mutation carriers and the implementation of screening strategies for these individuals. Yet there is, to date, no international consensus regarding screening strategies for asymptomatic carriers.Design: A comprehensive PubMed search from 1/1/2000 to 28/2/2018 was undertaken using multiple search terms and subsequently a manual review of references in identified papers to identify all clinically relevant cases and cohorts. In this review, the accumulated, published experience of phenotype and malignancy risks of individual SDH subunits is analysed. Where possible screening results for asymptomatic SDH mutation carriers have been analysed separately to define the penetrance in asymptomatic carriers (asymptomatic penetrance). Results:The combined data confirms that "asymptomatic penetrance" is highest for SDHD and when there is penetrance, the most likely site to develop a PGL is head and neck (SDHD) and extra-adrenal abdominal (SDHB). However, the risk in SDHB carriers of developing HNPGL is also high (35.5%) and a PCC is low (15.1%), and in SDHD carriers there is a high risk of developing a PCC (35.8%) or abdominal PGL (9.4%) and a small, but significant risk at other sympathetic sites. The data suggest that the risk of malignant transformation is the same for both PCC and extra-adrenal abdominal PGLs (30%-35%) in SDHB carriers. In SDHD carriers, the risk of malignant transformation was highest in HNPGLs (7.5%) and similar for sympathetic sites (3.8%-5.2%). Conclusions:Using this data, we suggest surveillance screening of asymptomatic carriers can be tailored to the underlying SDH subunit and review possible surveillance programmes. K E Y W O R D S imaging, MRI, paraganglioma, phaeochromocytoma, screening, SDH, succinate dehydrogenase, surveillance S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Tufton N, Sahdev A, Drake WM, Akker SA. Can subunit-specific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?. Clin Endocrinol. 2019;90:31-46. https://doi.

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“…A review of the literature identified 13 manuscripts that attempted to address this issue. Eight studies argued for surveillance to start before or at 10 years including one expert opinion, three case series with less than five patients, three retrospective studies with 32, 92 and 116 patients, respectively), and one case‐control study with 241 patients . Three reports recommended starting from the second decade of life (one systematic review of 95 papers suggesting a start age between 11‐20 years, one retrospective study with 91 patients suggesting an age of 27.1 years based on HNPGL penetrance calculations and one case series of three families suggested a starting age of 18 years for HNPGL screening) .…”

Section: Methodsmentioning

confidence: 99%

Clinical Practice Guidance: Surveillance for phaeochromocytoma and paraganglioma in paediatric succinate dehydrogenase gene mutation carriers

Wong

Andrews

Challis

et al. 2019

Clinical Endocrinology

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SummaryThe succinate dehydrogenase (SDH) enzyme complex functions as a key enzyme coupling the oxidation of succinate to fumarate in the citric acid cycle. Inactivation of this enzyme complex results in the cellular accumulation of the oncometabolite succinate, which is postulated to be a key driver in tumorigenesis. Succinate accumulation inhibits 2‐oxoglutarate‐dependent dioxygenases, including DNA and histone demethylase enzymes and hypoxic gene response regulators. Biallelic inactivation (typically resulting from one inherited and one somatic event) at one of the four genes encoding the SDH complex (SDHA/B/C/D) is the most common cause for SDH deficient (dSDH) tumours. Germline mutations in the SDHx genes predispose to a spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL), wild type gastrointestinal stromal tumours (wtGIST) and, less commonly, renal cell carcinoma and pituitary tumours. Furthermore, mutations in the SDHx genes, particularly SDHB, predispose to a higher risk of malignant PPGL, which is associated with a 5‐year mortality of 50%. There is general agreement that biochemical and imaging surveillance should be offered to asymptomatic carriers of SDHx gene mutations in the expectation that this will reduce the morbidity and mortality associated with dSDH tumours. However, there is no consensus on when and how surveillance should be performed in children and young adults. Here, we address the question: “What age should clinical, biochemical and radiological surveillance for PPGL be initiated in paediatric SDHx mutation carriers?”.

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SDHB-related pheochromocytoma and paraganglioma penetrance and genotype–phenotype correlations

Cited by 71 publications

References 43 publications

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Can subunit‐specific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?

Clinical Practice Guidance: Surveillance for phaeochromocytoma and paraganglioma in paediatric succinate dehydrogenase gene mutation carriers

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