Germline mutations and genotype–phenotype associations in head and neck paraganglioma patients with negative family history in China

Zhu, Weijun; Wang, Z.Y.; Chai, Yimin; Wang, X.W.; Chen, D.Y.; Wu, Hao

doi:10.1016/j.ejmg.2015.05.008

Cited by 16 publications

(13 citation statements)

References 29 publications

(49 reference statements)

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“…Only a few cases of PGL/PCC associated with SDHAF2 mutations have been described, and these account for <1% of all cases of PGL . Germline pathogenic variants in SDHAF2 have been seen only in association with HNPGLs . Kunst et al describe a large family of 16 patients, 11 with a HNPGL, primarily at carotid body and vagal locations.…”

Section: Phenotype Of Sdhx Mutation Carriersmentioning

confidence: 99%

“…According to Endocrine Society PGL/PCC guidelines, 18 F‐fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is the preferred imaging modality in SDHB‐ mutated PGL/PCC . Recent studies have shown that SDHx ‐related PGL/PCC might be better visualized by [ 68 Ga]‐DOTA(0)‐Tyr(3)‐octreotate ([GA]‐DOTATATE) PET/CT than 18 F‐FDG PET/CT, especially those located in the head and neck region as well as metastatic PGL/PCC . The sensitivity of FDG‐PET for SDHx related tumors varies between 83% and 100% …”

Section: Applications For Diagnostics Of Pgl/pccmentioning

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: Applications For Diagnostics Of Pgl/pccmentioning

confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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“…Homozygous missense (and one nonsense) mutations in SDHAF1 have been identified in affected subjects from six families, presenting with leukoencephalopathy; a peculiar hallmark was accumulation of lactate and succinate in the white matter [ 53 , 59 , 60 ]. To date, no mutation in SDHAF1 has been reported in patients with paraganglioma [ 61 ].…”

Section: Human Diseases Associated With CII Deficiency (Mim 252011)mentioning

confidence: 99%

Human diseases associated with defects in assembly of OXPHOS complexes

Ghezzi

Zeviani

2018

Essays in Biochemistry

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The structural biogenesis and functional proficiency of the multiheteromeric complexes forming the mitochondrial oxidative phosphorylation system (OXPHOS) require the concerted action of a number of chaperones and other assembly factors, most of which are specific for each complex. Mutations in a large number of these assembly factors are responsible for mitochondrial disorders, in most cases of infantile onset, typically characterized by biochemical defects of single specific complexes. In fact, pathogenic mutations in complex-specific assembly factors outnumber, in many cases, the repertoire of mutations found in structural subunits of specific complexes. The identification of patients with specific defects in assembly factors has provided an important contribution to the nosological characterization of mitochondrial disorders, and has also been a crucial means to identify a huge number of these proteins in humans, which play an essential role in mitochondrial bioenergetics. The wide use of next generation sequencing (NGS) has led to and will allow the identifcation of additional components of the assembly machinery of individual complexes, mutations of which are responsible for human disorders. The functional studies on patients’ specimens, together with the creation and characterization of in vivo models, are fundamental to better understand the mechanisms of each of them. A new chapter in this field will be, in the near future, the discovery of mechanisms and actions underlying the formation of supercomplexes, molecular structures formed by the physical, and possibly functional, interaction of some of the individual respiratory complexes, particularly complex I (CI), III (CIII), and IV (CIV).

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“…Analysis of data for 1045 patients in the Netherlands with this syndrome showed that mutations were most frequently found in SDHD (87.1%) but much less frequently in SDHAF2 (6.7%), SDHB (5.9%), and SDHC (0.3%) [271]. Mutation in the SDHD gene were also the most common in German patients [74], although among the germline mutations the most frequently recorded occurred in SDHB [61]. …”

Section: Genetic Classification Of Paragangliomas/pheochromo-cytomasmentioning

confidence: 99%

“…Mutations associated with pheochromocytomas and paragangliomas were subsequently found only in the genes for H-Ras and K-Ras of the Ras family [61, 106, 222–224]. …”

Section: Genetic Classification Of Paragangliomas/pheochromo-cytomasmentioning

confidence: 99%

Molecular markers of paragangliomas/pheochromocytomas

et al. 2017

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Paragangliomas/pheochromocytomas comprise rare tumors that arise from the extra-adrenal paraganglia, with an incidence of about 2 to 8 per million people each year. Approximately 40% of cases are due to genetic mutations in at least one out of more than 30 causative genes. About 2530% of pheochromocytomas/paragangliomas develop under the conditions of a hereditary tumor syndrome a third of which are caused by mutations in the VHL gene. Together, the gene mutations in this disorder have implicated multiple processes including signaling pathways, translation initiation, hypoxia regulation, protein synthesis, differentiation, survival, proliferation, and cell growth. The present review contemplates the mutations associated with the development of pheochromocytomas/paragangliomas and their potential to serve as specific markers of these tumors and their progression. These data will improve our understanding of the pathogenesis of these tumors and likely reveal certain features that may be useful for early diagnostics, malignancy prognostics, and the determination of new targets for disease therapeutics.

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Germline mutations and genotype–phenotype associations in head and neck paraganglioma patients with negative family history in China

Cited by 16 publications

References 29 publications

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Human diseases associated with defects in assembly of OXPHOS complexes

Molecular markers of paragangliomas/pheochromocytomas

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