SDHA mutated paragangliomas may be at high risk of metastasis

Tufton, Nicola; Ghelani, Rahul; Srirangalingam, Umasuthan; Kumar, Ajith; Drake, William M; Iacovazzo, Donato; Skordilis, Kassiani; Berney, Daniel M.; Al-Mrayat, Ma’en; Khoo, Bernard; Akker, Scott

doi:10.1530/erc-17-0030

Cited by 22 publications

(36 citation statements)

References 16 publications

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“…Metastatic disease was reported in 0% to 33% of PGL patients with SDHA mutations, although these reports included few patients (n = 4‐34) . GISTs and pituitary adenomas were reported in a small subset of patients .…”

Section: Phenotype Of Sdhx Mutation Carriersmentioning

confidence: 99%

“…28,29 Metastatic disease was reported in 0% to 33% of PGL patients with SDHA mutations, although these reports included few patients (n = 4-34). [31][32][33][34][35][36] GISTs and pituitary adenomas were reported in a small subset of patients. 24,31,32,37,38 In a large pediatric GIST study of Boikos et al, a SDHA mutation, germline or somatic, was the most common molecular subtype 39 Neuroblastoma was reported in one SDHA mutation carrier where it was possible to confirm loss of heterozygosity (LoH) in tumor tissue.…”

Section: Sdha Mutationsmentioning

confidence: 99%

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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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Section: Phenotype Of Sdhx Mutation Carriersmentioning

confidence: 99%

Section: Sdha Mutationsmentioning

confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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“…Several recent case reports or small cohorts of patients carrying SDHA mutations have been published . To date, the total number of cases reported is 93 with 41 different mutations.…”

Section: Surveillance Programmesmentioning

confidence: 99%

“…Table shows the number of patients that have developed PPGLs at different sites. Malignant disease was reported in 9.6% of patients, although of note the metastases seem to appear late . Median age at diagnosis was 40 years (range 12‐81 years).…”

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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“…The prevalence of malignancy is also variable, with a higher rate in SDHB (~30%) compared to SDHA, SDHC , and SDHD PPGLs (where occurrence of metastatic disease is rare, ~0–4%) [14]. Nevertheless, recent observations suggest that the rate of malignancy in SDHA PPGLs can be higher than previously expected and large scale studies are needed to establish the malignancy rate in these tumors (Pacak, unpublished observations) [15]. These distinguishing features illustrate that genotype alone cannot explain the entire clinical picture of SDHx -related PPGLs.…”

Section: Introductionmentioning

confidence: 99%

New Insights into the Nuclear Imaging Phenotypes of Cluster 1 Pheochromocytoma and Paraganglioma

Taïeb

Pacák

2017

Trends in Endocrinology & Metabolism

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Pheochromocytomas and paragangliomas (PPGLs) belong to the family of neural crest cell-derived neoplasms. In up to 70% of cases, they are associated with germline and somatic mutations in 15 well-characterized PPGL driver or fusions genes. PPGLs can be grouped into three main clusters, where cluster 1 represents PPGLs characterized by a pseudohypoxic signature. Although cluster 1 tumors share several common features, they exhibit unique behaviors. Here, we present unique insights into imaging phenotypes of cluster 1 PPGLs based on glucose uptake, catecholamine metabolism and somatostatin receptor expression. Recent data suggests that succinate is a major player in the imaging phenotype of succinate dehydrogenase-deficient PPGLs. This review emphasizes the emerging stromal cell-succinate interaction and highlights new perspectives in PPGL theranostics.

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SDHA mutated paragangliomas may be at high risk of metastasis

Cited by 22 publications

References 16 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?

New Insights into the Nuclear Imaging Phenotypes of Cluster 1 Pheochromocytoma and Paraganglioma

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