Chromosomal changes in sporadic and familial head and neck paragangliomas

Sevilla, María A.; Hermsen, Mario; Weiss, Marjan M.; Grimbergen, Anneliese; Balbı́n, Milagros; Llorente, José Luís; Rodrigo, Juan P.; Suárez, Carlos

doi:10.1016/j.otohns.2009.01.004

Cited by 15 publications

(19 citation statements)

References 20 publications

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“…The incidence of HNPGLs has a reported range of 1:30,000 to 1:1,000,00, comprising only 0.6% of all head and neck tumors (Chapman et al, 2010). In the head and neck region, they most commonly arise from the carotid body, followed by jugulotympanic, vagal, laryngeal, and aorticopulmonary paraganglia (Sevilla et al, 2009;Pellitteri et al, 2004;Baysal et al, 2002). However, HNPGLs arise mostly from the jugulotympanic body (n ¼ 21; 80.8%), and carotid (n ¼ 4; 15.4%),and vagal nerve (n ¼ 1; 3.8%) in our series.…”

Section: Discussionmentioning

confidence: 99%

“…Non-chromaffin paragangliomas (PGLs), which are rare, highly vascularized, and generally benign tumors, arise mainly in the neural crest chief cells of paraganglia, with an incidence of 1:30,000 to 1:1,000,00 (Sevilla et al, 2009) , (Pellitteri et al, 2004) , (Chapman et al, 2010). In the head and neck region, the carotid body (CB) is the largest of all paraganglia and is also the most common site of the tumors, followed by jugulotympanic, vagal, laryngeal, and aorticopulmonary paraganglia (Sevilla et al, 2009;Pellitteri et al, 2004;Baysal et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…In the head and neck region, the carotid body (CB) is the largest of all paraganglia and is also the most common site of the tumors, followed by jugulotympanic, vagal, laryngeal, and aorticopulmonary paraganglia (Sevilla et al, 2009;Pellitteri et al, 2004;Baysal et al, 2002). All types of PGLs can occur in both sporadic and hereditary forms.…”

Section: Introductionmentioning

confidence: 99%

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

Zhu

Wang

Chai

et al. 2015

European Journal of Medical Genetics

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Zhu

Wang

Chai

et al. 2015

European Journal of Medical Genetics

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“…Previous investigations, that utilized low density approaches, such as comparative genomic hybridization (CGH) and loss of heterozygosity analysis, revealed frequent deletions of chromosome arms 1p, 3q and 22q and multiple minimal overlapping regions of deletion in at least 16 chromosomes, particularly 1p, 3q, 11p/q, 17p and 22q, while the most common minimal regions of gain were in 1q, 7p, 12q and 19p [18, 52, 54]. The existence of recurrent losses and gains in several chromosomes suggests that multiple genes are inactivated or activated in PGLs.…”

Section: Discussionmentioning

confidence: 99%

Integrative genetic, epigenetic and pathological analysis of paraganglioma reveals complex dysregulation of NOTCH signaling

et al. 2013

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Head and neck paragangliomas, rare neoplasms of the paraganglia composed of nests of neurosecretory and glial cells embedded in vascular stroma, provide a remarkable example of organoid tumor architecture. To identify genes and pathways commonly deregulated in head and neck paraganglioma, we integrated high-density genome-wide copy number variation (CNV) analysis with microRNA and immunomorphological studies. Gene-centric CNV analysis of 24 cases identified a list of 104 genes most significantly targeted by tumor-associated alterations. The “NOTCH signaling pathway” was the most significantly enriched term in the list (P = 0.002 after Bonferroni or Benjamini correction). Expression of the relevant NOTCH pathway proteins in sustentacular (glial), chief (neuroendocrine) and endothelial cells was confirmed by immunohistochemistry in 47 head and neck paraganglioma cases. There were no relationships between level and pattern of NOTCH1/JAG2 protein expression and germline mutation status in the SDH genes, implicated in paraganglioma predisposition, or the presence/absence of immunostaining for SDHB, a surrogate marker of SDH mutations. Interestingly, NOTCH upregulation was observed also in cases with no evidence of CNVs at NOTCH signaling genes, suggesting altered epigenetic modulation of this pathway. To address this issue we performed microarray-based microRNA expression analyses. Notably 5 microRNAs (miR-200a,b,c and miR-34b,c), including those most downregulated in the tumors, correlated to NOTCH signaling and directly targeted NOTCH1 in in vitro experiments using SH-SY5Y neuroblastoma cells. Furthermore, lentiviral transduction of miR-200s and miR-34s in patient-derived primary tympano-jugular paraganglioma cell cultures was associated with NOTCH1 downregulation and increased levels of markers of cell toxicity and cell death. Taken together, our results provide an integrated view of common molecular alterations associated with head and neck paraganglioma and reveal an essential role of NOTCH pathway deregulation in this tumor type.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1165-y) contains supplementary material, which is available to authorized users.

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“…In addition, residues proximal to the Cys ligands of the Fe-S clusters have been mutated and shown to affect the assembly and catalytic properties of complex II. For example, SdhB Pro-197 is located adjacent to one of the Cys ligands of the [3Fe-4S] cluster and has been associated with paragangliomas in several studies (13,54,55,57). When the equivalent residue was mutated in E. coli QFR (60) or in Saccharomyces cerevisiae (61) or Caenorhabditis elegans (62) complex II, increased reactive oxygen species were produced, quinone reduction was significantly perturbed, and C. elegans had a shortened life span phenotypically similar to the SdhC mev-1 mutant, in which the [3Fe-4S]/quinone-binding domain is perturbed (63).…”

Section: Aberrant Complex II Activity Associated With Tumor Formationmentioning

confidence: 99%

Structural Basis for Malfunction in Complex II

Iverson

Maklashina

Cecchini

2012

Journal of Biological Chemistry

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Complex II couples oxidoreduction of succinate and fumarate at one active site with that of quinol/quinone at a second distinct active site over 40 Å away. This process links the Krebs cycle to oxidative phosphorylation and ATP synthesis. The pathogenic mutation or inhibition of human complex II or its assembly factors is often associated with neurodegeneration or tumor formation in tissues derived from the neural crest. This brief overview of complex II correlates the clinical presentations of a large number of symptom-associated alterations in human complex II activity and assembly with the biochemical manifestations of similar alterations in the complex II homologs from Escherichia coli. These analyses provide clues to the molecular basis for diseases associated with aberrant complex II function.Over the past 6 decades, complex II (succinate dehydrogenase, succinate:quinone oxidoreductase (SQR) 3 ) has been at the forefront in the discovery of redox cofactors involved in bioenergetics. Helmut Beinert noted that in the 1950s-1960s, complex II was instrumental in the discovery of covalently bound flavin, tightly bound iron, and acid-labile sulfur associated with Fe-S clusters and bound ubiquinone of the mitochondrial respiratory chain (1). In 1995, a mutation of human complex II was the first report of a nuclear gene mutation shown to cause a mitochondrial respiratory chain deficiency (2). More recently, germ-line mutations in complex II have been found to be associated with hereditary tumors, suggesting that complex II genes may act as tumor suppressors (3).Complex II enzymes ( Fig. 1A) are heterotetramers containing two soluble subunits (SdhA (flavoprotein) and SdhB (Fe-S protein)) and two integral membrane subunits (SdhC and SdhD). This architecture houses two distinct active sites, and the coordinated catalysis at these sites links two key biological pathways, i.e. succinate oxidation to the Krebs cycle and quinone reduction to the electron transport chain. The SdhA subunit harbors a covalently attached FAD redox moiety and the dicarboxylate-binding site (Fig. 1B), where succinate is oxidized to fumarate. The product protons of this oxidation are transferred to bulk solvent, and fumarate acts as the next substrate in the Krebs cycle. The product electrons are transferred over 40 Å via three Fe-S clusters in the SdhB protein. These electrons act as co-substrates at the second active site, located at the interface of the integral membrane subunits. At this quinonereducing site (Fig. 1C), 2H ϩ and 2eϪ reduce ubiquinone to ubiquinol. The resultant quinol pool supports ATP synthesis by oxidative phosphorylation.The complex II superfamily contains both SQRs and quinol: fumarate reductases (QFRs). QFRs are enzymes that are kinetically poised to catalyze quinol oxidation and fumarate reduction as part of anaerobic electron transport chains. Both enzymes have evolved to function optimally in the physiological niche in which they are expressed. SQR and QFR are capable of functionally replacing each other in vivo in E...

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Chromosomal changes in sporadic and familial head and neck paragangliomas

Cited by 15 publications

References 20 publications

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

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

Integrative genetic, epigenetic and pathological analysis of paraganglioma reveals complex dysregulation of NOTCH signaling

Structural Basis for Malfunction in Complex II

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