SDHD

Gene Summary

Gene:SDHD; succinate dehydrogenase complex, subunit D, integral membrane protein
Aliases: PGL, CBT1, CWS3, PGL1, QPs3, SDH4, cybS, CII-4
Location:11q23
Summary:This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial
HPRD
Source:NCBIAccessed: 18 March, 2015

Ontology:

What does this gene/protein do?
Show (14)
Pathways:What pathways are this gene/protein implicaed in?
Show (3)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 18 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 18 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SDHD (cancer-related)

Bayley JP, Oldenburg RA, Nuk J, et al.
Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations.
BMC Med Genet. 2014; 15:111 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The SDHD gene encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme and tumor suppressor, succinate dehydrogenase. Mutations in this gene show a remarkable pattern of parent-of-origin related tumorigenesis, with almost all SDHD-related cases of head and neck paragangliomas and pheochromocytomas attributable to paternally-transmitted mutations.
METHODS: Here we explore the underlying molecular basis of three cases of paraganglioma or pheochromocytoma that came to our attention due to apparent maternal transmission of an SDHD mutation. We used DNA analysis of family members to establish the mode of inheritance of each mutation. Genetic and immunohistochemical studies of available tumors were then carried out to confirm SDHD-related tumorigenesis.
RESULTS: We found convincing genetic and immunohistochemical evidence for the maternally-related occurrence of a case of pheochromocytoma, and suggestive evidence in a case of jugular paraganglioma. The third case appears to be a phenocopy, a sporadic paraganglioma in an SDHD mutation carrier with no immunohistochemical or DNA evidence to support a causal link between the mutation and the tumor. Microsatellite analysis in the tumor of patient 1 provided evidence for somatic recombination and loss of the paternal region of chromosome 11 including SDHD and the maternal chromosome including the centromere and the p arm.
CONCLUSIONS: Transmission of SDHD mutations via the maternal line can, in rare cases, result in tumorigenesis. Despite this finding, the overwhelming majority of carriers of maternally-transmitted mutations will remain tumor-free throughout life.

Zdrojowy-Wełna A, Bednarek-Tupikowska G
Challenges in the diagnosis of pheochromocytoma and paraganglioma syndrome.
Neuro Endocrinol Lett. 2014; 35(5):355-8 [PubMed] Related Publications
OBJECTIVES: Adrenal pheochromocytomas are rare neuroendocrine tumours, however their prevalence is probably underestimated - in some series 50% were diagnosed at autopsy. The clinical presentation varies among patients, that is why diagnosis might be difficult to establish. Pheochromocytoma may coexist with paraganglioma and when paraganglioma is diagnosed, the patient should be screened for pheochromocytoma too, especially in people with hypertension. We present a case of woman with pheochromocytoma, but diagnosed after incidence of stroke, who had also paraganglioma in the past. Additionally, a teratoma was diagnosed simultaneously.
CASE REPORT: 49-year old woman with hypertension was referred to the Department of Endocrinology, Diabetology and Isotope Therapy in Wrocław with suspected pheochromocytoma. She was operated twice because of paraganglioma of the right and left carotid artery, second operation was complicated with stroke. After administration of anticoagulants a bleeding from gastrointestinal tract occurred. During diagnostic process CT of the abdomen showed tumour in the right adrenal gland and a tumour in pelvis. Significantly elevated catecholamines and their metabolites in blood and urine confirmed the diagnosis of pheochromocytoma. Both tumours were removed surgically, the second was teratoma maturum. Genetic screening for hereditary pheochromocytoma was proceeded. A mutation in SDHD gene was revealed in patient's DNA and subsequently in blood samples of her sister and daughter.
CONCLUSIONS: Occurrence of paraganglioma with hypertension suggest need of screening for pheochromocytoma-paraganglioma syndrome, especially in case of paragangliomas in family history. Early treatment is crucial to avoid life-threatening cardiovascular complications. The association between pheochromocytoma and teratoma is unclear.

Weinhold N, Jacobsen A, Schultz N, et al.
Genome-wide analysis of noncoding regulatory mutations in cancer.
Nat Genet. 2014; 46(11):1160-5 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Cancer primarily develops because of somatic alterations in the genome. Advances in sequencing have enabled large-scale sequencing studies across many tumor types, emphasizing the discovery of alterations in protein-coding genes. However, the protein-coding exome comprises less than 2% of the human genome. Here we analyze the complete genome sequences of 863 human tumors from The Cancer Genome Atlas and other sources to systematically identify noncoding regions that are recurrently mutated in cancer. We use new frequency- and sequence-based approaches to comprehensively scan the genome for noncoding mutations with potential regulatory impact. These methods identify recurrent mutations in regulatory elements upstream of PLEKHS1, WDR74 and SDHD, as well as previously identified mutations in the TERT promoter. SDHD promoter mutations are frequent in melanoma and are associated with reduced gene expression and poor prognosis. The non-protein-coding cancer genome remains widely unexplored, and our findings represent a step toward targeting the entire genome for clinical purposes.

Bachurska S, Staykov D, Belovezhdov V, et al.
Bilateral pheochromocytoma/intra-adrenal paraganglioma in von Hippel-Lindau patient causing acute myocardial infarction.
Pol J Pathol. 2014; 65(1):78-82 [PubMed] Related Publications
A 26-year-old male presented to the emergency department complaining of obstipation, severe headache and abdominal pain. An autopsy revealed bilateral pheochromocytoma and acute myocardial infarction. The tumor cells showed positive immunoreactivity of both chromogranin A and synaptophysin and were negative for adrenocortical markers such as SF-1, c17, scc, 3-HSD as well as SDHB, suggesting a germline mutation of the gene SDHB or SDHD. Molecular genetic analyses did not show a mutation in these two genes, but a mutation in the VHL gene, in exon 3: VHL c.499C>T. This is a missense mutation and causes an amino acid change (Arg167Trp).

Kidd M, Modlin IM, Drozdov I
Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors.
BMC Genomics. 2014; 15:595 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
BACKGROUND: Tumor transcriptomes contain information of critical value to understanding the different capacities of a cell at both a physiological and pathological level. In terms of clinical relevance, they provide information regarding the cellular "toolbox" e.g., pathways associated with malignancy and metastasis or drug dependency. Exploration of this resource can therefore be leveraged as a translational tool to better manage and assess neoplastic behavior. The availability of public genome-wide expression datasets, provide an opportunity to reassess neuroendocrine tumors at a more fundamental level. We hypothesized that stringent analysis of expression profiles as well as regulatory networks of the neoplastic cell would provide novel information that facilitates further delineation of the genomic basis of small intestinal neuroendocrine tumors.
RESULTS: We re-analyzed two publically available small intestinal tumor transcriptomes using stringent quality control parameters and network-based approaches and validated expression of core secretory regulatory elements e.g., CPE, PCSK1, secretogranins, including genes involved in depolarization e.g., SCN3A, as well as transcription factors associated with neurodevelopment (NKX2-2, NeuroD1, INSM1) and glucose homeostasis (APLP1). The candidate metastasis-associated transcription factor, ST18, was highly expressed (>14-fold, p < 0.004). Genes previously associated with neoplasia, CEBPA and SDHD, were decreased in expression (-1.5 - -2, p < 0.02). Genomic interrogation indicated that intestinal tumors may consist of two different subtypes, serotonin-producing neoplasms and serotonin/substance P/tachykinin lesions. QPCR validation in an independent dataset (n = 13 neuroendocrine tumors), confirmed up-regulated expression of 87% of genes (13/15).
CONCLUSIONS: An integrated cellular transcriptomic analysis of small intestinal neuroendocrine tumors identified that they are regulated at a developmental level, have key activation of hypoxic pathways (a known regulator of malignant stem cell phenotypes) as well as activation of genes involved in apoptosis and proliferation. Further refinement of these analyses by RNAseq studies of large-scale databases will enable definition of individual master regulators and facilitate the development of novel tissue and blood-based tools to better understand diagnose and treat tumors.

Richter S, Peitzsch M, Rapizzi E, et al.
Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency.
J Clin Endocrinol Metab. 2014; 99(10):3903-11 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
CONTEXT: Mutations of succinate dehydrogenase A/B/C/D genes (SDHx) increase susceptibility to development of pheochromocytomas and paragangliomas (PPGLs), with particularly high rates of malignancy associated with SDHB mutations.
OBJECTIVE: We assessed whether altered succinate dehydrogenase product-precursor relationships, manifested by differences in tumor ratios of succinate to fumarate or other metabolites, might aid in identifying and stratifying patients with SDHx mutations.
DESIGN, SETTING, AND PATIENTS: PPGL tumor specimens from 233 patients, including 45 with SDHx mutations, were provided from eight tertiary referral centers for mass spectrometric analyses of Krebs cycle metabolites.
MAIN OUTCOME MEASURE: Diagnostic performance of the succinate:fumarate ratio for identification of pathogenic SDHx mutations.
RESULTS: SDH-deficient PPGLs were characterized by 25-fold higher succinate and 80% lower fumarate, cis-aconitate, and isocitrate tissue levels than PPGLs without SDHx mutations. Receiver-operating characteristic curves for use of ratios of succinate to fumarate or to cis-aconitate and isocitrate to identify SDHx mutations indicated areas under curves of 0.94 to 0.96; an optimal cut-off of 97.7 for the succinate:fumarate ratio provided a diagnostic sensitivity of 93% at a specificity of 97% to identify SDHX-mutated PPGLs. Succinate:fumarate ratios were higher in both SDHB-mutated and metastatic tumors than in those due to SDHD/C mutations or without metastases.
CONCLUSIONS: Mass spectrometric-based measurements of ratios of succinate:fumarate and other metabolites in PPGLs offer a useful method to identify patients for testing of SDHx mutations, with additional utility to quantitatively assess functionality of mutations and metabolic factors responsible for malignant risk.

Clark GR, Sciacovelli M, Gaude E, et al.
Germline FH mutations presenting with pheochromocytoma.
J Clin Endocrinol Metab. 2014; 99(10):E2046-50 [PubMed] Related Publications
CONTEXT: At least a third of the patients with pheochromocytoma (PCC) or paraganglioma (PGL) harbor an underlying germline mutation in a known PCC/PGL gene. Mutations in genes (SDHB, SDHD, SDHC, and SDHA) encoding a component of the tricarboxylic acid cycle, succinate dehydrogenase (SDH), are a major cause of inherited PCC and PGL. SDHB mutations are also, albeit less frequently, associated with inherited renal cell carcinoma. Inactivation of SDH and another tricarboxylic acid cycle component, fumarate hydratase (FH), have both been associated with abnormalities of cellular metabolism, responsible for the activation of hypoxic gene response pathways and epigenetic alterations (eg, DNA methylation). However, the clinical phenotype of germline mutations in SDHx genes and FH is usually distinct, with FH mutations classically associated with hereditary cutaneous and uterine leiomyomatosis and renal cell carcinoma, although recently an association with PCC/PGL has been reported.
OBJECTIVE AND DESIGN: To identify potential novel PCC/PGL predisposition genes, we initially undertook exome resequencing studies in a case of childhood PCC, and subsequently FH mutation analysis in a further 71 patients with PCC, PGL, or head and neck PGL.
RESULTS: After identifying a candidate FH missense mutation in the exome study, we then detected a further candidate missense mutation (p.Glu53Lys) by candidate gene sequencing. In vitro analyses demonstrated that both missense mutations (p.Cys434Tyr and p.Glu53Lys) were catalytically inactive.
CONCLUSIONS: These findings 1) confirm that germline FH mutations may present, albeit rarely with PCC or PGL; and 2) extend the clinical phenotype associated with FH mutations to pediatric PCC.

Holt DE, Henthorn P, Howell VM, et al.
Succinate dehydrogenase subunit D and succinate dehydrogenase subunit B mutation analysis in canine phaeochromocytoma and paraganglioma.
J Comp Pathol. 2014; 151(1):25-34 [PubMed] Related Publications
Phaeochromocytomas (PCs) are tumours of the adrenal medulla chromaffin cells. Paragangliomas (PGLs) arise in sympathetic ganglia (previously called extra-adrenal PCs) or in non-chromaffin parasympathetic ganglia cells that are usually non-secretory. Parenchymal cells from these tumours have a common embryological origin from neural crest ectoderm. Several case series of canine PCs and PGLs have been published and a link between the increased incidence of chemoreceptor neoplasia in brachycephalic dog breeds and chronic hypoxia has been postulated. A similar link to hypoxia in man led to the identification of germline heterozygous mutations in the gene encoding succinate dehydrogenase subunit D (SDHD) and subsequently SDHA, SDHB and SDHC in similar tumours. We investigated canine PCs (n = 6) and PGLs (n = 2) for SDHD and SDHB mutations and in one PGL found a somatic SDHD mutation c.365A>G (p.Lys122Arg) in exon 4, which was not present in normal tissue from this brachycephalic dog. Two PCs were heterozygous for both c.365A>G (p.Lys122Arg) mutation and an exon 3 silent variant c.291G>A. We also identified the heterozygous SDHB exon 2 mutation c.113G>A (p.Arg38Gln) in a PC. These results illustrate that genetic mutations may underlie tumourigenesis in canine PCs and PGLs. The spontaneous nature of these canine diseases and possible association of PGLs with hypoxia in brachycephalic breeds may make them an attractive model for studying the corresponding human tumours.

Canu L, Rapizzi E, Zampetti B, et al.
Pitfalls in genetic analysis of pheochromocytomas/paragangliomas-case report.
J Clin Endocrinol Metab. 2014; 99(7):2321-6 [PubMed] Related Publications
CONTEXT: About 35% of patients with pheochromocytoma/paraganglioma carry a germline mutation in one of the 10 main susceptibility genes. The recent introduction of next-generation sequencing will allow the analysis of all these genes in one run. When positive, the analysis is generally unequivocal due to the association between a germline mutation and a concordant clinical presentation or positive family history. When genetic analysis reveals a novel mutation with no clinical correlates, particularly in the presence of a missense variant, the question arises whether the mutation is pathogenic or a rare polymorphism.
OBJECTIVE: We report the case of a 35-year-old patient operated for a pheochromocytoma who turned out to be a carrier of a novel SDHD (succinate dehydrogenase subunit D) missense mutation. With no positive family history or clinical correlates, we decided to perform additional analyses to test the clinical significance of the mutation.
METHODS: We performed in silico analysis, tissue loss of heterozygosity analysis, immunohistochemistry, Western blot analysis, SDH enzymatic assay, and measurement of the succinate/fumarate concentration ratio in the tumor tissue by tandem mass spectrometry.
RESULTS: Although the in silico analysis gave contradictory results according to the different methods, all the other tests demonstrated that the SDH complex was conserved and normally active. We therefore came to the conclusion that the variant was a nonpathogenic polymorphism.
CONCLUSIONS: Advancements in technology facilitate genetic analysis of patients with pheochromocytoma but also offer new challenges to the clinician who, in some cases, needs clinical correlates and/or functional tests to give significance to the results of the genetic assay.

Else T, Marvin ML, Everett JN, et al.
The clinical phenotype of SDHC-associated hereditary paraganglioma syndrome (PGL3).
J Clin Endocrinol Metab. 2014; 99(8):E1482-6 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
CONTEXT: Mutations in the genes encoding subunits of the succinate dehydrogenase complex cause hereditary paraganglioma syndromes. Although the phenotypes associated with the more commonly mutated genes, SDHB and SDHD, are well described, less is known about SDHC-associated paragangliomas.
OBJECTIVE: To describe functionality, penetrance, number of primary tumors, biological behavior, and location of paragangliomas associated with SDHC mutations.
DESIGN: Families with an SDHC mutation were identified through a large cancer genetics registry. A retrospective chart review was conducted with a focus on patient and tumor characteristics. In addition, clinical reports on SDHC-related paragangliomas were identified in the medical literature to further define the phenotype and compare findings.
SETTING: A cancer genetics clinic and registry at a tertiary referral center.
PATIENTS: Eight index patients with SDHC-related paraganglioma were identified.
RESULTS: Three of the eight index patients had mediastinal paraganglioma and four of the eight patients had more than one paraganglioma. Interestingly, the index patients were the only affected individuals in all families. When combining these index cases with reported cases in the medical literature, the mediastinum is the second most common location for SDHC-related paraganglioma (10% of all tumors), occurring in up to 13% of patients.
CONCLUSIONS: Our findings suggest that thoracic paragangliomas are common in patients with SDHC mutations, and imaging of this area should be included in surveillance of mutation carriers. In addition, the absence of paragangliomas among at-risk relatives of SDHC mutation carriers suggests a less penetrant phenotype as compared to SDHB and SDHD mutations.

Pai R, Manipadam MT, Singh P, et al.
Usefulness of Succinate dehydrogenase B (SDHB) immunohistochemistry in guiding mutational screening among patients with pheochromocytoma-paraganglioma syndromes.
APMIS. 2014; 122(11):1130-5 [PubMed] Related Publications
Genetic testing of pheochromocytomas (PCC) and paragangliomas (PGL), although expensive, is gradually becoming a part of the routine laboratory investigation for patients with PCC-PGL syndrome. Recently, Succinate dehydrogenase B (SDHB) immunochemistry has been shown to be an excellent indicator of germline mutations in the SDH genes and could help significantly reduce cost. This study assesses the utility of SDHB immunohistochemical analysis when used to guide genetic analysis, with emphasis on cost benefits it could provide in a resource-limited setting. Forty-four cases of PCC/PGL characterized by genetic analysis were included to determine their SDHB expression pattern by immunohistochemistry. SDHB antibody expression was negative among three cases each, with SDHB and SDHD mutations. Immunohistochemistry results were positive for all three cases of RET, a single case of neurofibromatosis and for two cases with Von Hippel-Lindau (VHL) mutations while the remaining two cases with VHL mutations showed a diffuse 'cytoplasmic blush'. Thirty of the remaining 31 samples demonstrated positive staining and were negative for mutations, while a lone sample that was negative for staining and mutation was not included in the final analysis as the internal control for the sample was not adequately stained. Cost analysis in our settings showed that triaging with SDHB immunohistochemistry could potentially reduce costs by USD 320-500 per patient. SDHB immunohistochemistry, when used as a guide to genetic testing, can significantly reduce the effort, time and costs of testing among patients with PCC-PGL, a huge benefit in resource limited settings.

Casey R, Garrahy A, Tuthill A, et al.
Universal genetic screening uncovers a novel presentation of an SDHAF2 mutation.
J Clin Endocrinol Metab. 2014; 99(7):E1392-6 [PubMed] Related Publications
CONTEXT: Hereditary pheochromocytoma/paraganglioma (PC/PGL) accounts for up to 60% of previously considered sporadic tumors. Guidelines suggest that phenotype should guide genetic testing. Next-generation sequencing technology can simultaneously sequence 9 of the 18 known susceptibility genes in a timely, cost-efficient manner.
OBJECTIVE: Our aim was to confirm that universal screening is superior to targeted testing in patients with histologically confirmed PC and PGL.
METHODS: In two tertiary referral hospitals in Ireland, NGS was carried out on all histologically confirmed cases of PC/PGL diagnosed between 2004 and 2013. The following susceptibility genes were sequenced: VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. A multiplex ligation-dependent probe amplification analysis was performed in VHL, SDHB, SDHC, SDHD, and SDHAF2 genes to detect deletions and duplications.
RESULTS: A total of 31 patients were tested, 31% (n = 10) of whom were found to have a genetic mutation. Of those patients with a positive genotype, phenotype predicted genotype in only 50% (n = 5). Significant genetic mutations that would have been missed in our cohort by phenotypic evaluation alone include a mutation in TMEM127, two mutations in SDHAF2, and two mutations in RET. Target testing would have identified three of the latter mutations based on age criteria. However, 20% of patients (n = 2) would not have satisfied any criteria for targeted testing including one patient with a novel presentation of an SDHAF2 mutation.
CONCLUSION: This study supports the value of universal genetic screening for all patients with PC/PGL.

Welander J, Andreasson A, Juhlin CC, et al.
Rare germline mutations identified by targeted next-generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma.
J Clin Endocrinol Metab. 2014; 99(7):E1352-60 [PubMed] Related Publications
CONTEXT: Pheochromocytomas and paragangliomas have a highly diverse genetic background, with a third of the cases carrying a germline mutation in 1 of 14 identified genes.
OBJECTIVE: This study aimed to evaluate next-generation sequencing for more efficient genetic testing of pheochromocytoma and paraganglioma and to establish germline and somatic mutation frequencies for all known susceptibility genes.
DESIGN: A targeted next-generation sequencing approach on an Illumina MiSeq instrument was used for a mutation analysis in 86 unselected pheochromocytoma and paraganglioma tumor samples. The study included the genes EGLN1, EPAS1, KIF1Bβ, MAX, MEN1, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL. RESULTS were verified in tumor and constitutional DNA with Sanger sequencing.
RESULTS: In all cases with clinical syndromes or known germline mutations, a mutation was detected in the expected gene. Among 68 nonfamilial tumors, 32 mutations were identified in 28 of the samples (41%), including germline mutations in EGLN1, KIF1Bβ, SDHA, SDHB, and TMEM127 and somatic mutations in EPAS1, KIF1Bβ, MAX, NF1, RET, and VHL, including one double monoallelic EPAS1 mutation.
CONCLUSIONS: Targeted next-generation sequencing proved to be fast and cost effective for the genetic analysis of pheochromocytoma and paraganglioma. More than half of the tumors harbored mutations in the investigated genes. Notably, 7% of the apparently sporadic cases carried germline mutations, highlighting the importance of comprehensive genetic testing. KIF1Bβ, which previously has not been investigated in a large cohort, appears to be an equally important tumor suppressor as MAX and TMEM127 and could be considered for genetic testing of these patients.

Gill AJ, Toon CW, Clarkson A, et al.
Succinate dehydrogenase deficiency is rare in pituitary adenomas.
Am J Surg Pathol. 2014; 38(4):560-6 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Germline mutations in the succinate dehydrogenase genes (SDHA, SDHB, SDHC, and SDHD) are established as causes of pheochromocytoma/paraganglioma, renal carcinoma, and gastrointestinal stromal tumor. It has recently been suggested that pituitary adenomas may also be a component of this syndrome. We sought to determine the incidence of SDH mutation in pituitary adenomas. We performed screening immunohistochemistry for SDHB and SDHA on all available pituitary adenomas resected at our institution from 1998 to 2012. In those patients with an abnormal pattern of staining, we then performed SDH mutation analysis on DNA extracted from paraffin-embedded tissue, fresh frozen tissue, and peripheral blood. One of 309 adenomas (0.3%) demonstrated an abnormal pattern of staining, a 30 mm prolactin-producing tumor from a 62-year-old man showing loss of staining for both SDHA and SDHB. Examination of paraffin-embedded and frozen tissues confirmed double-hit inactivating somatic SDHA mutations (c.725_736del and c.989_990insTA). Neither of these mutations was present in the germline. We conclude that, although pathogenic SDH mutation may occur in pituitary adenomas and can be identified by immunohistochemistry, it appears to be a very rare event and can occur in the absence of germline mutation. SDH-deficient pituitary adenomas may be larger and more likely to produce prolactin than other pituitary adenomas. Unless suggested by family history and physical examination, it is difficult to justify screening for SDH mutations in pituitary adenomas. Surveillance programs for patients with SDH mutation may be tailored to include the possibility of pituitary neoplasia; however, this is likely to be a low-yield strategy.

Crona J, Nordling M, Maharjan R, et al.
Integrative genetic characterization and phenotype correlations in pheochromocytoma and paraganglioma tumours.
PLoS One. 2014; 9(1):e86756 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: About 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS. Selective screening for germline mutations is routinely performed in clinical management of these diseases. Testing for somatic alterations is not performed on a regular basis because of limitations in interpreting the results.
AIM: The purpose of the study was to investigate genetic events and phenotype correlations in a large cohort of PCC and PGL tumours.
METHODS: A total of 101 tumours from 89 patients with PCC and PGL were re-sequenced for a panel of 10 disease causing genes using automated Sanger sequencing. Selected samples were analysed with Multiplex Ligation-dependent Probe Amplification and/or SNParray.
RESULTS: Pathogenic genetic variants were found in tumours from 33 individual patients (37%), 14 (16%) were discovered in constitutional DNA and 16 (18%) were confirmed as somatic. Loss of heterozygosity (LOH) was observed in 1/1 SDHB, 11/11 VHL and 3/3 NF1-associated tumours. In patients with somatic mutations there were no recurrences in contrast to carriers of germline mutations (P = 0.022). SDHx/VHL/EPAS1 associated cases had higher norepinephrine output (P = 0.03) and lower epinephrine output (P<0.001) compared to RET/NF1/H-RAS cases.
CONCLUSION: Somatic mutations are frequent events in PCC and PGL tumours. Tumour genotype may be further investigated as prognostic factors in these diseases. Growing evidence suggest that analysis of tumour DNA could have an impact on the management of these patients.

Millán-Uclés A, Díaz-Castro B, García-Flores P, et al.
A conditional mouse mutant in the tumor suppressor SdhD gene unveils a link between p21(WAF1/Cip1) induction and mitochondrial dysfunction.
PLoS One. 2014; 9(1):e85528 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Mutations in mitochondrial complex II (MCII; succinate dehydrogenase, Sdh) genes cause familiar pheochromocytoma/paraganglioma tumors. Several mechanisms have been proposed to account for Sdh-mutation-induced tumorigenesis, the most accepted of which is based on the constitutive expression of the hypoxia-inducible factor 1α (Hif1α) at normal oxygen tension, a theory referred to as "pseudo-hypoxic drive". Other molecular processes, such as oxidative stress, apoptosis, or chromatin remodeling have been also proposed to play a causative role. Nevertheless, the actual contribution of each of these mechanisms has not been definitively established. Moreover, the biological factors that determine the tissue-specificity of these tumors have not been identified. In this work, we made use of the inducible SDHD-ESR mouse, a conditional mutant in the SdhD gene, which encodes the small subunit of MCII, and that acts as a tumor suppressor gene in humans. The analysis of the Hif1α pathway in SDHD-ESR tissues and in two newly derived cell lines after complete SdhD loss -a requirement for hereditary paraganglioma type-1 tumor formation in humans- partially recapitulated the "pseudo-hypoxic" response and rendered inconsistent results. Therefore, we performed microarray analysis of adrenal medulla and kidney in order to identify other early gene expression changes elicited by SdhD deletion. Our results revealed that each mutant tissue displayed different variations in their gene expression profiles affecting to different biological processes. However, we found that the Cdkn1a gene was up-regulated in both tissues. This gene encodes the cyclin-dependent kinase inhibitor p21(WAF1/Cip1), a factor implicated in cell cycle, senescence, and cancer. The two SDHD-ESR cell lines also showed accumulation of this protein. This new and unprecedented evidence for a link between SdhD dysfunction and p21(WAF1/Cip1) will open new avenues for the study of the mechanisms that cause tumors in Sdh mutants. Finally, we discuss the actual role of Hif1α in tumorigenesis.

Bickmann JK, Sollfrank S, Schad A, et al.
Phenotypic variability and risk of malignancy in SDHC-linked paragangliomas: lessons from three unrelated cases with an identical germline mutation (p.Arg133*).
J Clin Endocrinol Metab. 2014; 99(3):E489-96 [PubMed] Related Publications
CONTEXT: Mutations in the four subunits of succinate dehydrogenase (SDH) are the cause for the hereditary paraganglioma (PGL) syndrome types 1-4 and are associated with multiple and recurrent pheochromocytomas and PGLs. SDHC mutations most frequently result in benign, nonfunctional head-and neck PGLs (HNPGLs). The malignant potential of SDHC mutations remains unclear to date.
OBJECTIVES: We report a patient with malignant PGL carrying a SDHC mutation and compare her case with two others of the same genotype but presenting with classic benign HNPGLs. Loss of heterozygosity (LOH) was demonstrated in the malignant PGL tissue.
DESIGN: In three unrelated patients referred for routine genetic testing, SDHB, SDHC, and SDHD genes were sequenced, and gross deletions were excluded by multiplex ligation-dependent probe amplification (MLPA). LOH was determined by pyrosequencing-based allele quantification and SDHB immunohistochemistry.
RESULTS: In a patient with a nonfunctioning thoracic PGL metastatic to the bone, the lungs, and mediastinal lymph nodes, we detected the SDHC mutation c.397C>T predicting a truncated protein due to a premature stop codon (p.Arg133*). We demonstrated LOH and loss of SDHB protein expression in the malignant tumor tissue. The two other patients also carried c.397C>T, p.Arg133*; they differed from each other with respect to their tumor characteristics, but both showed benign HNPGLs.
CONCLUSIONS: We describe the first case of a malignant PGL with distant metastases caused by a SDHC germline mutation. The present case shows that SDHC germline mutations can have highly variable phenotypes and may cause malignant PGL, although malignancy is probably rare.

Blanchet EM, Gabriel S, Martucci V, et al.
18F-FDG PET/CT as a predictor of hereditary head and neck paragangliomas.
Eur J Clin Invest. 2014; 44(3):325-32 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: Hereditary head and neck paragangliomas (HNPGLs) account for at least 35% of all HNPGLs, most commonly due to germline mutations in SDHx susceptibility genes. Several studies about sympathetic paragangliomas have shown that (18)F-FDG PET/CT was not only able to detect and localize tumours, but also to characterize tumours ((18)F-FDG uptake being linked to SDHx mutations). However, the data concerning (18)F-FDG uptake specifically in HNPGLs have not been addressed. The aim of this study was to evaluate the relationship between (18)F-FDG uptake and the SDHx mutation status in HNPGL patients.
METHODS: (18)F-FDG PET/CT from sixty HNPGL patients were evaluated. For all lesions, we measured the maximum standardized uptake values (SUVmax), and the uptake ratio defined as HNPGL-SUVmax over pulmonary artery trunk SUVmean (SUVratio). Tumour sizes were assessed on radiological studies.
RESULTS: Sixty patients (53.3% with SDHx mutations) were evaluated for a total of 106 HNPGLs. HNPGLs-SUVmax and SUVratio were highly dispersed (1.2-30.5 and 1.0-17.0, respectively). The HNPGL (18)F-FDG uptake was significantly higher in SDHx versus sporadic tumours on both univariate and multivariate analysis (P = 0.002). We developed two models for calculating the probability of a germline SDHx mutation. The first one, based on a per-lesion analysis, had an accuracy of 75.5%. The second model, based on a per-patient analysis, had an accuracy of 80.0%.
CONCLUSIONS: (18)F-FDG uptake in HNPGL is strongly dependent on patient genotype. Thus, the degree of (18)F-FDG uptake in these tumours can be used clinically to help identify patients in whom SDHx mutations should be suspected.

Kugelberg J, Welander J, Schiavi F, et al.
Role of SDHAF2 and SDHD in von Hippel-Lindau associated pheochromocytomas.
World J Surg. 2014; 38(3):724-32 [PubMed] Related Publications
BACKGROUND: 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. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and are 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 both in patients with PCCs and in patients with PGLs.
MATERIALS AND METHODS: Because loss of 11q is a common event in VHL-associated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In the present 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.
RESULTS AND CONCLUSIONS: LOH was found in more than 50 % of the VHL-associated PCCs, and was correlated with 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 indicates that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.

Imperiale A, Moussallieh FM, Sebag F, et al.
A new specific succinate-glutamate metabolomic hallmark in SDHx-related paragangliomas.
PLoS One. 2013; 8(11):e80539 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Paragangliomas (PGLs) are frequently associated with germline mutations in genes involved in energy metabolism. The purpose of the present study was to assess whether the tumor metabolomic profile of patients with hereditary and apparently sporadic PGLs enables the distinction of different subtypes of tumors. Twenty-eight unrelated patients with a histological diagnosis of PGLs were included in the present study. Twelve had germline mutations in SDHx genes (5 SDHB, 7 SDHD), 6 VHL, and 10 were apparently sporadic. Intact tumor samples from these patients (one per patient) were evaluated with (1)H high-resolution magic angle spinning (HRMAS) NMR spectroscopy. SDHx-related tumors were characterized by an increase in succinate levels in comparison to other tumor subtypes (p = 0.0001 vs VHL and p = 0.000003 vs apparently sporadic). Furthermore, we found significantly lower values of glutamate in SDHx-related tumors compared to other subtypes (p = 0.0007 vs VHL and p = 0.003 vs apparently sporadic). Moreover, SDHx-tumors also exhibited lower values of ATP/ADP/AMP (p = 0.01) compared to VHL. VHL tumors were found to have the highest values of glutathione (GSH) compared to other tumors. Based on 4 metabolites (succinate, glutamate, GSH, and ATP/ADP/AMP), tumors were accurately distinguished from the other ones on both 3- and 2-class PLS-DA models. The present study shows that HRMAS NMR spectroscopy is a very promising method for investigating the metabolomic profile of various PGLs. The present data suggest the existence of a specific succinate-glutamate hallmark of SDHx PGLs. The relevance of such a metabolomic hallmark is expected to be very useful in designing novel treatment options as well as improving the diagnosis and follow-up of these tumors, including metastatic ones.

Bacca A, Chiacchio S, Zampa V, et al.
Role of 18F-DOPA PET/CT in diagnosis and follow-up of adrenal and extra-adrenal paragangliomas.
Clin Nucl Med. 2014; 39(1):14-20 [PubMed] Related Publications
PURPOSE: The objective of this study was to establish the clinical value of F-DOPA PET/CT in patients with adrenal and extra-adrenal paragangliomas (PGLs).
METHODS: Twenty-six consecutive patients with suspected or recurrent PGL underwent MR (and/or CT) and F-DOPA PET/CT. Histopathology confirmation was obtained in 20 cases. Genetic analysis on known susceptibility genes for PGL (VHL, RET, SDHx, TMEM127) was available in 13 patients.
RESULTS: Fourteen patients were affected by PGL (8 with head/neck location, 6 with abdominal/thoracic location), whereas 12 showed masses of other origin. Three patients proved to be SDHD, 1 SDHB, 2 SDHC, and 1 TMEM127 mutation carriers. F-DOPA PET/CT showed pathological uptake in 13 of 26 patients. The procedure identified all PGLs except one with bone metastases (previous malignant adrenal PGL). No uptake was found in patients without proven PGL. Thus, in the whole group, F-DOPA PET/CT sensitivity was 92.8%, and specificity was 100% with positive and negative predictive values of 100% and 92.3%, respectively. Total diagnostic accuracy was 96.2%. In the head/neck subgroup, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were 100%. In the abdominal location, sensitivity was 80% and specificity was 100%, and positive and negative predictive values were 100% and 91.7%, respectively. Abdominal diagnostic accuracy was 93.7%. Radiotracer uptake was superimposable in head/neck PGLs versus abdominal PGLs and in mutated versus wild-type patients.
CONCLUSIONS: The high diagnostic performance of F-DOPA PET/CT showed this technique to be a useful tool in detecting PGLs, above all those located at the head/neck site, regardless of the genetic pattern.

Lendvai N, Pawlosky R, Bullova P, et al.
Succinate-to-fumarate ratio as a new metabolic marker to detect the presence of SDHB/D-related paraganglioma: initial experimental and ex vivo findings.
Endocrinology. 2014; 155(1):27-32 [PubMed] Related Publications
Pheochromocytomas (PHEOs) and paragangliomas (PGLs; extra-adrenal tumors) are rare neuroendocrine chromaffin cell tumors with a hereditary background in about 30%-35%. Those caused by succinate dehydrogenase subunit B (SDHB) germline mutations are associated with a high metastatic potential and ultimately higher patient mortality. Succinate dehydrogenase converts succinate to fumarate, uniquely linking the Krebs cycle and oxidative phosphorylation. SDH mutations result in the accumulation of succinate associated with various metabolic disturbances and the shift to aerobic glycolysis in tumor tissue. In the present study, we measured succinate and fumarate levels in mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells and in 10 apparently sporadic, 10 SDHB-, 5 SDHD-, and 2 neurofibromatosis 1-related PHEOs/PGLs and plasma samples using mass spectrometry. We found that the succinate-to-fumarate ratio was significantly higher in the SDHB- and SDHD-related PGLs than in apparently sporadic and neurofibromatosis 1-related PHEOs/PGLs (P = .0376). To further support our data, we silenced SDHB expression in MPC and MTT cells and evaluated the succinate and fumarate levels. Compared with control samples, SDHB-silenced MTT cells also showed an increase in the succinate-to-fumarate ratio (MTT cells: 2.45 vs 7.53), similar to the findings in SDHB-related PGLs. The present findings for the first time demonstrate a significantly increased succinate-to-fumarate ratio in SDHB/D-related PGLs and thus suggest this ratio may be used as a new metabolic marker for the detection of SDHB/D-related PHEOs/PGLs.

Bausch B, Wellner U, Bausch D, et al.
Long-term prognosis of patients with pediatric pheochromocytoma.
Endocr Relat Cancer. 2014; 21(1):17-25 [PubMed] Related Publications
A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.

Ellis RJ, Patel D, Prodanov T, et al.
The presence of SDHB mutations should modify surgical indications for carotid body paragangliomas.
Ann Surg. 2014; 260(1):158-62 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to determine whether the genetic background of the disease should be incorporated into treatment decision making.
BACKGROUND: Carotid body paragangliomas are rare tumors that often affect patients with genetic mutations of the succinate dehydrogenase complex (SDHx). Despite growing evidence that germ line genetic mutations alter the aggressiveness of paragangliomas, treatment decisions are currently based only on clinical symptoms and tumor size in patients with carotid body paragangliomas.
METHODS: Retrospective analysis of 34 patients with carotid body paragangliomas who underwent genetic testing and surgical treatment. Recurrence was defined by the return of locoregional disease and/or development of distant metastases. Clinical characteristics and genetic testing results were analyzed as predictors of patient outcomes.
RESULTS: Thirty-four patients underwent 41 primary carotid body paraganglioma resections (median follow-up time of 42 months, range: 1-293). Overall survival was 91.2%. Twelve patients had germ line mutations in SDHB, 17 in SDHD, and 5 carried no known mutation. Surgical resection of larger tumors was associated with higher operative complications (odds ratio: 5.4, P = 0.05). Tumor size at resection was significantly smaller in patients with SDHB mutations than in patients with non-SDHB mutations (2.1 vs 3.3 cm, P = 0.02). Patients with a mutation in the SDHB gene also had significantly worse disease-free survival compared with patients without an SDHB gene mutation (P = 0.03).
CONCLUSIONS: Mutations in the SDHB gene are associated with worse disease-free survival after resection in patients with carotid body paragangliomas despite earlier intervention. This suggests that a more aggressive surgical approach is warranted in patients with SDHB mutations.

Huguet I, Walker L, Karavitaki N, et al.
Dandy-Walker malformation, papillary thyroid carcinoma, and SDHD-associated paraganglioma syndrome.
J Clin Endocrinol Metab. 2013; 98(12):4595-6 [PubMed] Related Publications

Andreasson A, Kiss NB, Caramuta S, et al.
The VHL gene is epigenetically inactivated in pheochromocytomas and abdominal paragangliomas.
Epigenetics. 2013; 8(12):1347-54 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Pheochromocytoma (PCC) and abdominal paraganglioma (PGL) are neuroendocrine tumors that present with clinical symptoms related to increased catecholamine levels. About a third of the cases are associated with constitutional mutations in pre-disposing genes, of which some may also be somatically mutated in sporadic cases. However, little is known about inactivating epigenetic events through promoter methylation in these very genes. Using bisulphite pyrosequencing we assessed the methylation density of 11 PCC/PGL disease genes in 96 tumors (83 PCCs and 13 PGLs) and 34 normal adrenal references. Gene expression levels were determined by quantitative RT-PCR. Both tumors and normal adrenal samples exhibited low methylation index (MetI) in the EGLN1 (PDH2), MAX, MEN1, NF1, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127 promoters, not exceeding 10% in any of the samples investigated. Aberrant RET promoter methylation was observed in two cases only. For the VHL gene we found increased MetI in tumors as compared with normal adrenals (57% vs. 27%; P<0.001), in malignant vs. benign tumors (63% vs. 55%; P<0.05), and in PGL vs. PCC (66% vs. 55%; P<0.0005). Decreased expression of the VHL gene was observed in all tumors compared with normal adrenals (P<0.001). VHL MetI and gene expressions were inversely correlated (R = -0.359, P<0.0001). Our results show that the VHL gene promoter has increased methylation compared with normal adrenals (MetI>50%) in approximately 75% of PCCs and PGLs investigated, highlighting the role of VHL in the development of these tumors.

Papathomas TG, de Krijger RR, Tischler AS
Paragangliomas: update on differential diagnostic considerations, composite tumors, and recent genetic developments.
Semin Diagn Pathol. 2013; 30(3):207-23 [PubMed] Related Publications
Recent developments in molecular genetics have expanded the spectrum of disorders associated with pheochromocytomas (PCCs) and extra-adrenal paragangliomas (PGLs) and have increased the roles of pathologists in helping to guide patient care. At least 30% of these tumors are now known to be hereditary, and germline mutations of at least 10 genes are known to cause the tumors to develop. Genotype-phenotype correlations have been identified, including differences in tumor distribution, catecholamine production, and risk of metastasis, and types of tumors not previously associated with PCC/PGL are now considered in the spectrum of hereditary disease. Important new findings are that mutations of succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD, and SDHAF2 (collectively "SDHx") are responsible for a large percentage of hereditary PCC/PGL and that SDHB mutations are strongly correlated with extra-adrenal tumor location, metastasis, and poor prognosis. Further, gastrointestinal stromal tumors and renal tumors are now associated with SDHx mutations. A PCC or PGL caused by any of the hereditary susceptibility genes can present as a solitary, apparently sporadic, tumor, and substantial numbers of patients presenting with apparently sporadic tumors harbor occult germline mutations of susceptibility genes. Current roles of pathologists are differential diagnosis of primary tumors and metastases, identification of clues to occult hereditary disease, and triaging of patients for optimal genetic testing by immunohistochemical staining of tumor tissue for the loss of SDHB and SDHA protein. Diagnostic pitfalls are posed by morphological variants of PCC/PGL, unusual anatomic sites of occurrence, and coexisting neuroendocrine tumors of other types in some hereditary syndromes. These pitfalls can be avoided by judicious use of appropriate immunohistochemical stains. Aside from loss of staining for SDHB, criteria for predicting risk of metastasis are still controversial, and "malignancy" is diagnosed only after metastases have occurred. All PCCs/PGLs are considered to pose some risk of metastasis, and long-term follow-up is advised.

McInerney-Leo AM, Marshall MS, Gardiner B, et al.
Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas.
Clin Endocrinol (Oxf). 2014; 80(1):25-33 [PubMed] Related Publications
BACKGROUND: Genetic testing is recommended when the probability of a disease-associated germline mutation exceeds 10%. Germline mutations are found in approximately 25% of individuals with phaeochromcytoma (PCC) or paraganglioma (PGL); however, genetic heterogeneity for PCC/PGL means many genes may require sequencing. A phenotype-directed iterative approach may limit costs but may also delay diagnosis, and will not detect mutations in genes not previously associated with PCC/PGL.
OBJECTIVE: To assess whether whole exome sequencing (WES) was efficient and sensitive for mutation detection in PCC/PGL.
METHODS: Whole exome sequencing was performed on blinded samples from eleven individuals with PCC/PGL and known mutations. Illumina TruSeq (Illumina Inc, San Diego, CA, USA) was used for exome capture of seven samples, and NimbleGen SeqCap EZ v3.0 (Roche NimbleGen Inc, Basel, Switzerland) for five samples (one sample was repeated). Massive parallel sequencing was performed on multiplexed samples. Sequencing data were called using Genome Analysis Toolkit and annotated using annovar. Data were assessed for coding variants in RET, NF1, VHL, SDHD, SDHB, SDHC, SDHA, SDHAF2, KIF1B, TMEM127, EGLN1 and MAX. Target capture of five exome capture platforms was compared.
RESULTS: Six of seven mutations were detected using Illumina TruSeq exome capture. All five mutations were detected using NimbleGen SeqCap EZ v3.0 platform, including the mutation missed using Illumina TruSeq capture. Target capture for exons in known PCC/PGL genes differs substantially between platforms. Exome sequencing was inexpensive (<$A800 per sample for reagents) and rapid (results <5 weeks from sample reception).
CONCLUSION: Whole exome sequencing is sensitive, rapid and efficient for detection of PCC/PGL germline mutations. However, capture platform selection is critical to maximize sensitivity.

Castelblanco E, Santacana M, Valls J, et al.
Usefulness of negative and weak-diffuse pattern of SDHB immunostaining in assessment of SDH mutations in paragangliomas and pheochromocytomas.
Endocr Pathol. 2013; 24(4):199-205 [PubMed] Related Publications
This is a confirmatory study about usefulness of SDHB and SDHA immunostaining in assessment of SDH mutations in paragangliomas and pheochromocytomas. Paraganglioma/pheochromocytoma syndrome (PGL/PCC syndrome) consists of different entities, associated with germline mutations in five different genes: SDHD, SDHAF2, SDHC, SDHA and SDHB. It has been suggested that negative immunostaining of SDHB can be taken as an indicator of the presence of a mutation in one of the five SDH genes. We have performed SDHB and SDHA immunohistochemical staining in a series of paragangliomas and pheochromocytomas from 64 patients. The patients had been previously checked for mutations in SDHD, SDHC and SDHB, but also for mutation in RET and VHL. All 14 patients with SDH mutations (9 with SDHB and 5 with SDHD mutations) exhibited negative or weak-diffuse SDHB staining pattern in tumour tissue, whereas cells of the 23 RET mutated and 8 VHL mutated tumours showed a positive SDHB immunostaining. Sixteen of the patients that did not exhibit a mutation in any gene showed positive SDHB immunostaining in tumour tissue, while only three of the patients without mutation exhibited negative staining. All patients exhibited positive pattern of SDHA immunostaining. The results confirm the value of SDHB immunohistochemical status in assessment of germline mutations in PGL/PCC syndrome.

Papathomas TG, Gaal J, Corssmit EP, et al.
Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: a clinicopathological and molecular analysis.
Eur J Endocrinol. 2014; 170(1):1-12 [PubMed] Related Publications
OBJECTIVE: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated.
DESIGN AND METHODS: Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC.
RESULTS: Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression.
CONCLUSIONS: These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. SDHD, Cancer Genetics Web: http://www.cancer-genetics.org/SDHD.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 18 March, 2015     Cancer Genetics Web, Established 1999