Distinct Clinical Features of Paraganglioma Syndromes Associated With &lt;EMPH TYPE="ITAL"&gt;SDHB&lt;/EMPH&gt; and &lt;EMPH TYPE="ITAL"&gt;SDHD&lt;/EMPH&gt; Gene Mutations

Neumann, Hartmut P. H.; Pawlu, Christian; Pęczkowska, Mariola; Bausch, Birke; McWhinney, Sarah R.; Mureşan, Mihaela; Buchta, Mary; Franke, Gerlind; Klisch, Joachim; Bley, Thorsten Alexander; Hoegerle, Stefan; Boedeker, Carsten C.; Opocher, Giuseppe; Schipper, Jörg; Januszewicz, Andrzej; Eng, Charis

doi:10.1001/jama.292.8.943

Cited by 838 publications

(916 citation statements)

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“…SDHC mutations or deletions are rare and have so far been associated only with familial and sporadic head and neck paraganglioma (Baysal et al, 2004;Schiavi et al, 2005). In addition, two comprehensive comparison studies of tumours with SDHB or SDHD mutations have been performed and several obvious differences have been identified (Neumann et al, 2004;Benn, 2006). It is noteworthy that SDHD mutations are mostly related to head and neck paraganglioma whereas SDHB mutations can be seen at higher frequencies in adrenal and extra-adrenal phaeochromocytoma as well as in non-paraganglioma tumours.…”

Section: Mitochondrial Tumour Suppressor Genesmentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.

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Section: Mitochondrial Tumour Suppressor Genesmentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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“…With the current data related to discoveries of new genes in the pathogenesis of PCCs and PGLs, the proportion of hereditary tumors is estimated to be around 30-35% [2][3][4]. The vast majority of these patients belong to one of the following syndromes: von Hippel-Lindau (VHL) [5], multiple endocrine neoplasia type 2 (MEN 2) [6], von Recklinghausen (NF1) [7] or pheochromocytomaparaganglioma syndrome (PGL types 1-4) [8][9][10][11], which are caused by germline mutations in VHL, RET, NF1 and SDHx (SDHA, SDHB, SDHC, SDHD, and SDHAF2/SDH5), respectively. In addition, germline mutations in KIF1Bβ have been found in patients with PCCs, neuroblastomas and other neural and non-neural tumors [12,13].…”

Section: Introductionmentioning

confidence: 99%

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

et al. 2013

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Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel Lindau (VHL) syndrome. In VHL, only about 30% of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought for. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found in both patients with PCCs and PGLs. Since loss of 11q is a common event in VHLassociated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In this study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation as well as mRNA expression of SDHAF2 and SDHD was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. LOH was found in more than 50% of the VHL-associated PCCs, and was correlated to a significant decrease (p<0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression.In addition, the lack of mutations and promoter methylation in the investigated samples indicate that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.3

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“…Malignancy, defined as metastatic paraganglioma, can occur in SDHD-linked patients but is most common in SDHB mutation carriers. 7,8 We have offered genetic testing to asymptomatic relatives of patients with SDHD mutations at Leiden University Medical Center (LUMC) since 2002, and more recently, for SDHB, SDHC or SDHAF2 mutations. We have now evaluated the outcome of SDHD/SDHB testing and surveillance, with the aim of establishing the prevalence of paragangliomas in asymptomatic carriers.…”

Section: Introductionmentioning

confidence: 99%

High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations

Heesterman

Bayley²,

Tops

et al. 2012

Eur J Hum Genet

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Hereditary paraganglioma is a benign tumor syndrome with an age-dependent penetrance. Carriers of germline mutations in the SDHB or SDHD genes may develop parasympathetic paragangliomas in the head and neck region or sympathetic catecholamine-secreting abdominal and thoracic paragangliomas (pheochromocytomas). In this study, we aimed to establish paraganglioma risk in 101 asymptomatic germline mutation carriers and evaluate the results of our surveillance regimen. Asymptomatic carriers of an SDHD or SDHB mutation were included once disease status was established by MRI diagnosis. Clinical surveillance revealed a head and neck paraganglioma in 28 of the 47 (59.6%) asymptomatic SDHD mutation carriers. Risk of tumor development was significantly lower in SDHB mutation carriers: 2/17 (11.8%, P ¼ 0.001). Sympathetic paragangliomas were encountered in two SDHD mutation carriers and in one SDHB mutation carrier. In conclusion, asymptomatic carriers of an SDHD mutation are at a high risk for occult parasympathetic paraganglioma. SDHB carrier risk is considerably lower, consistent with lower penetrance of SDHB mutations. For both syndromes, the risk of symptomless sympathetic paragangliomas is small.

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Distinct Clinical Features of Paraganglioma Syndromes Associated With <EMPH TYPE="ITAL">SDHB</EMPH> and <EMPH TYPE="ITAL">SDHD</EMPH> Gene Mutations

Cited by 838 publications

References 40 publications

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations

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