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Jeanpierre Bayley - One of the best experts on this subject based on the ideXlab platform.
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variant type is associated with disease characteristics in SDHB sdhc and sdhd linked phaeochromocytoma paraganglioma
Journal of Medical Genetics, 2020Co-Authors: Jeanpierre Bayley, Birke Bausch, David B Ascher, Douglas E V Pires, Johannes A Rijken, Leonie T Van Hulsteijn, Jeroen C Jansen, Frederik J Hes, Erik F Hensen, Eleonora P M CorssmitAbstract:Background Pathogenic germline variants in subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) are broadly associated with disease subtypes of phaeochromocytoma–paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype. Methods Three independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the SDHB, SDHC or SDHD genes. Results Truncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of SDHD truncating variants had a significantly higher risk for PPGL (p Conclusions SDHD truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to SDHB. We propose that surveillance and counselling of carriers of SDHD should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.
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non pheochromocytoma pcc paraganglioma pgl tumors in patients with succinate dehydrogenase related pcc pgl syndromes a clinicopathological and molecular analysis
European Journal of Endocrinology, 2014Co-Authors: Thomas G Papathomas, Jeanpierre Bayley, Lindsey Oudijk, Jose Gaal, Esther Korpershoek, Eleonora P M Corssmit, Ketil Heimdal, Hans Morreau, Marieke F Van Dooren, Konstantinos PapaspyrouAbstract:textabstractObjective: 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.
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The role of complex II in disease.
Biochimica et biophysica acta, 2012Co-Authors: Attje S. Hoekstra, Jeanpierre BayleyAbstract:Abstract Genetically defined mitochondrial deficiencies that result in the loss of complex II function lead to a range of clinical conditions. An array of tumor syndromes caused by complex II-associated gene mutations, in both succinate dehydrogenase and associated accessory factor genes ( SDHA , SDHB , SDHC , SDHD , SDHAF1 , SDHAF2 ), have been identified over the last 12 years and include hereditary paraganglioma–pheochromocytomas, a diverse group of renal cell carcinomas, and a specific subtype of gastrointestinal stromal tumors (GIST). In addition, congenital complex II deficiencies due to inherited homozygous mutations of the catalytic components of complex II (SDHA and SDHB) and the SDHAF1 assembly factor lead to childhood disease including Leigh syndrome, cardiomyopathy and infantile leukodystrophies. The role of complex II subunit gene mutations in tumorigenesis has been the subject of intensive research and these data have led to a variety of compelling hypotheses. Among the most widely researched are the stabilization of hypoxia inducible factor 1 under normoxia, and the generation of reactive oxygen species due to defective succinate:ubiquinone oxidoreductase function. Further progress in understanding the role of complex II in disease, and in the development of new therapeutic approaches, is now being hampered by the lack of relevant cell and animal models. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.
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High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations.
European journal of human genetics : EJHG, 2012Co-Authors: Berdine L. Heesterman, Jeanpierre Bayley, Frederik J Hes, Eleonora P M Corssmit, Carli M. J. Tops, Bernadette T J Van Brussel, Jaap F. Hamming, Andel G. L. Van Der Mey, Jeroen C JansenAbstract: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=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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Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma
Familial Cancer, 2011Co-Authors: Erik F Hensen, Jeanpierre BayleyAbstract:The last 10 years have seen enormous progress in the field of paraganglioma and pheochromocytoma genetics. The identification of the first gene related to paraganglioma, SDHD , encoding a subunit of mitochondrial succinate dehydrogenase (SDH), was quickly followed by the identification of mutations in SDHC and SDHB . Very recently several new SDH-related genes have been discovered. The SDHAF2 gene encodes an SDH co-factor related to the function of the SDHA subunit, and is currently exclusively associated with head and neck paragangliomas. SDHA itself has now also been identified as a paraganglioma gene, with the recent identification of the first mutation in a patient with extra-adrenal paraganglioma. Another SDH-related co-factor, SDHAF1 , is not currently known to be a tumor suppressor, but may shed some light on the mechanisms of tumorigenesis. An entirely novel gene associated with adrenal pheochromocytoma, TMEM127 , suggests that other new paraganglioma susceptibility genes may await discovery. In addition to these recent discoveries, new techniques related to mutation analysis, including genetic analysis algorithms, SDHB immunohistochemistry, and deletion analysis by MLPA have improved the efficiency and accuracy of genetic analysis. However, many intriguing questions remain, such as the striking differences in the clinical phenotype of genes that encode proteins with an apparently very close functional relationship, and the lack of expression of SDHD and SDHAF2 mutations when inherited via the maternal line. Little is still known of the origins and causes of truly sporadic tumors, and the role of oxygen in the relationships between high-altitude, familial and truly sporadic paragangliomas remains to be elucidated.
Eamonn R Maher - One of the best experts on this subject based on the ideXlab platform.
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Familial wild-type gastrointestinal stromal tumour in association with germline truncating variants in both SDHA and PALB2
European Journal of Human Genetics, 2021Co-Authors: James Whitworth, Ruth T Casey, Philip S. Smith, Olivier Giger, Jose Ezequiel Martin, Graeme Clark, Jaqueline Cook, Marlee S. Fernando, Phillipe Taniere, Eamonn R MaherAbstract:Gastrointestinal stromal tumour (GIST) is a mesenchymal neoplasm arising in the gastrointestinal tract. A rare subset of GISTs are classified as wild-type GIST (wtGIST) and these are frequently associated with germline variants that affect the function of cancer predisposition genes such as the succinate dehydrogenase subunit genes ( SDHA, SDHB, SDHC, SDHD ) or NF1 . However, despite this high heritability, familial clustering of wtGIST is extremely rare. Here, we report a mother–son diad who developed wtGIST at age 66 and 34 years, respectively. Comprehensive genetic testing revealed germline truncating variants in both SDHA (c.1534C>T (p.Arg512*)) and PALB2 (c.3113G>A (p.Trp1038*)) in both affected individuals. The mother also developed breast ductal carcinoma in-situ at age 70 years. Immunohistochemistry and molecular analysis of the wtGISTs revealed loss of SDHB expression and loss of the wild-type SDHA allele in tumour material. No allele loss was detected at PALB2 suggesting that wtGIST tumourigenesis was principally driven by succinate dehydrogenase deficiency. However, we speculate that the presence of multilocus inherited neoplasia alleles syndrome (MINAS) in this family might have contributed to the highly unusual occurrence of familial wtGIST. Systematic reporting of tumour risks and phenotypes in individuals with MINAS will facilitate the clinical interpretation of the significance of this diagnosis, which is becoming more frequent as strategies for genetic testing for hereditary cancer becomes more comprehensive.
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Germline SDHB Mutations and Familial Renal Cell Carcinoma
Journal of the National Cancer Institute, 2008Co-Authors: Christopher J. Ricketts, Dewi Astuti, Farida Latif, Emma R Woodward, Pip Killick, Mark R. Morris, Eamonn R MaherAbstract:Familial renal cell carcinoma (RCC) is a heterogeneous disorder that is most commonly caused by germline mutations in the VHL, MET, and FLCN genes or by constitutional chromosome 3 translocations. However, for many patients with familial RCC, the genetic basis of the disease is undefined. We investigated whether germline mutations in fumarate hydratase (FH) or succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD) were associated with RCC susceptibility in 68 patients with no clinical evidence of an RCC susceptibility syndrome. No mutations in FH, SDHC, or SDHD were identified in probands, but 3 of the 68 (4.4%) probands had a germline SDHB mutation. Patients with a germline SDHB mutation presented with familial RCC (n = 1) or bilateral RCC (n = 2) and no personal or family history of pheochromocytoma or head and neck paraganglioma. Age at diagnosis of RCC in SDHB mutation carriers ranged from 24 to 73 years. These findings 1) demonstrate that patients with suspected inherited RCC should be examined for germline SDHB mutations, 2) suggest that all identified SDHB mutation carriers should be offered surveillance for RCC, and 3) provide a further link between familial RCC and activation of hypoxic-gene response pathways.
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gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma
American Journal of Human Genetics, 2001Co-Authors: Dewi Astuti, Charis Eng, Farida Latif, Ashraf Dallol, Patricia L M Dahia, Fiona Douglas, Emad George, Filip Skoldberg, Eystein S Husebye, Eamonn R MaherAbstract:The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.
Esther Korpershoek - One of the best experts on this subject based on the ideXlab platform.
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loss of maternal chromosome 11 is a signature event in sdhaf2 sdhd and vhl related paragangliomas but less significant in SDHB related paragangliomas
Oncotarget, 2017Co-Authors: Attje S. Hoekstra, Esther Korpershoek, Jeroen C Jansen, Frederik J Hes, Erik F Hensen, Eleonora P M Corssmit, Ekaterina S Jordanova, Anouk N A Van Der Horstschrivers, Cees J Cornelisse, Henricus P M KunstAbstract:// Attje S. Hoekstra 1 , Erik F. Hensen 2 , Ekaterina S. Jordanova 3 , Esther Korpershoek 4 , Anouk N.A. van der Horst-Schrivers 5 , Cees Cornelisse 3 , Eleonora P.M. Corssmit 6 , Frederik J. Hes 7 , Jeroen C. Jansen 8 , Henricus P.M. Kunst 9 , Henri J.L.M. Timmers 10 , Adrian Bateman 11 , Diana Eccles 12 , Judith V.M.G. Bovee 3 , Peter Devilee 1, 3 , Jean-Pierre Bayley 1 1 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands 2 Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands 3 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands 4 Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands 5 Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 6 Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands 7 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands 8 Department of Otorhinolaryngology, Leiden University Medical Center, Leiden, The Netherlands 9 Department of Otorhinolaryngology, Head and Neck Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands 10 Department of Medicine, Division of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands 11 Department of Cellular Pathology, University Hospital Southampton, Southampton, UK 12 University of Southampton School of Medicine, Cancer Sciences Division, Somers Cancer Research Building, Southampton, UK Correspondence to: Jean-Pierre Bayley, email: J.P.L.Bayley@lumc.nl Peter Devilee, email: P.Devilee@lumc.nl Keywords: paraganglioma, pheochromocytoma, succinate dehydrogenase, Von Hippel-Lindau, loss of heterozygosity Received: September 06, 2016 Accepted: January 04, 2017 Published: January 14, 2017 ABSTRACT Germline mutations in the succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD, SDHAF2) or Von Hippel-Lindau (VHL) genes cause hereditary paraganglioma/pheochromocytoma. While SDHB (1p36) and VHL (3p25) are associated with autosomal dominant disease, SDHD (11q23) and SDHAF2 (11q13) show a remarkable parent-of-origin effect whereby tumor formation is almost completely dependent on paternal transmission of the mutant allele. Loss of the entire maternal copy of chromosome 11 occurs frequently in SDHD -linked tumors, and has been suggested to be the basis for this typical inheritance pattern. Using fluorescent in situ hybridization, microsatellite marker and SNP array analysis, we demonstrate that loss of the entire copy of chromosome 11 is also frequent in SDHAF2 -related PGLs, occurring in 89% of tumors. Analysis of two imprinted differentially methylated regions (DMR) in 11p15, H19-DMR and KvDMR, showed that this loss always affected the maternal copy of chromosome 11. Likewise, loss of maternal chromosome 11p15 was demonstrated in 85% of SDHD and 75% of VHL -related PGLs/PCCs. By contrast, both copies of chromosome 11 were found to be retained in 62% of SDHB -mutated PGLs/PCCs, while only 31% showed loss of maternal chromosome 11p15. Genome-wide copy number analysis revealed frequent loss of 1p in SDHB mutant tumors and show greater genomic instability compared to SDHD and SDHAF2 . These results show that loss of the entire copy of maternal chromosome 11 is a highly specific and statistically significant event in SDHAF2 , SDHD and VHL -related PGLs/PCCs, but is less significant in SDHB -mutated tumors, suggesting that these tumors have a distinct genetic etiology.
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Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations
Genetics in Medicine, 2015Co-Authors: Lucie Evenepoel, Thomas G Papathomas, Alexandre Persu, Esther Korpershoek, Ronald R. Krijger, Niels Krol, Winand N.m. DinjensAbstract:The tricarboxylic acid, or Krebs, cycle is central to the cellular metabolism of sugars, lipids, and amino acids; it fuels the mitochondrial respiratory chain for energy generation. In the past decade, mutations in the Krebs-cycle enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase have been documented to be causally involved in carcinogenesis. This review is focused on the relationship between SDH mutations and the carcinogenic phenotype. The succinate dehydrogenase complex catalyzes the oxidation of succinate to fumarate; mutations in its subunits SDHA , SDHB , SDHC , and SDHD , and in the assembly factor SDHAF2 , result in syndromes with distinct tumor types, including pheochromocytoma/paraganglioma, gastrointestinal stromal tumor, and, less often, renal-cell carcinoma and pituitary adenoma. In this study we collected all previously reported SDH mutations with the aim of defining their nature and tumor spectrum. In addition, genotype–phenotype correlations as well as mechanisms of biallelic inactivation were analyzed in the SDH -deficient setting. Finally, we performed bioinformatics analysis using SIFT, Polyphen2, and Mutation Assessor to predict the functional impact of nonsynonymous mutations. The prediction of the latter was further compared with available SDHA and/or SDHB immunohistochemistry data. Genet Med 17 8, 610–620.
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non pheochromocytoma pcc paraganglioma pgl tumors in patients with succinate dehydrogenase related pcc pgl syndromes a clinicopathological and molecular analysis
European Journal of Endocrinology, 2014Co-Authors: Thomas G Papathomas, Jeanpierre Bayley, Lindsey Oudijk, Jose Gaal, Esther Korpershoek, Eleonora P M Corssmit, Ketil Heimdal, Hans Morreau, Marieke F Van Dooren, Konstantinos PapaspyrouAbstract:textabstractObjective: 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.
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SDHB immunohistochemistry a useful tool in the diagnosis of carney stratakis and carney triad gastrointestinal stromal tumors
Modern Pathology, 2011Co-Authors: Jose Gaal, Francien H Van Nederveen, Paraskevi Xekouki, Esther Korpershoek, Constantine A. Stratakis, Evan R. Ball, Maya B. Lodish, Isaac Levy, Aidan J Carney, Michael Den A BakkerAbstract:Mutations in the tumor suppressor genes SDHB, SDHC, and SDHD (or collectively SDHx) cause the inherited paraganglioma syndromes, characterized by pheochromocytomas and paragangliomas. However, other tumors have been associated with SDHx mutations, such as gastrointestinal stromal tumors (GISTs) specifically in the context of Carney–Stratakis syndrome. Previously, we have shown that SDHB immunohistochemistry is a reliable technique for the identification of pheochromocytomas and paragangliomas caused by SDHx mutations. We hypothesized that GISTs in patients with SDHx mutations would be negative immunohistochemically for SDHB as well. Four GISTs from patients with Carney–Stratakis syndrome and six from patients with Carney triad were investigated by SDHB immunohistochemistry. Five GISTs with KIT or PDGFRA gene mutations were used as controls. In addition, SDHB immunohistochemistry was performed on 42 apparently sporadic GISTs. In cases in which the SDHB immunohistochemistry was negative, mutational analysis of SDHB, SDHC, and SDHD was performed. All GISTs from patients with Carney–Stratakis syndrome and Carney triad were negative for SDHB immunohistochemically. In one patient with Carney–Stratakis syndrome, a germline SDHB mutation was found (p.Ser92Thr). The five GISTs with a KIT or PDGFRA gene mutation were all immunohistochemically positive for SDHB. Of the 42 sporadic tumors, one GIST was SDHB-negative. Mutational analysis of this tumor did not reveal an SDHx mutation. All SDHB-negative GISTs were located in the stomach, had an epithelioid morphology, and had no KIT or PDGFRA mutations. We show that Carney–Stratakis syndrome- and Carney-triad-associated GISTs are negative by immunohistochemistry for SDHB in contrast to KIT- or PDGFRA-mutated GISTs and a majority of sporadic GISTs. We suggest that GISTs of epithelioid cell morphology are tested for SDHB immunohistochemically. In case of negative SDHB staining in GISTs, Carney–Stratakis syndrome or Carney triad should be considered and appropriate clinical surveillance should be instituted.
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SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinal stromal tumors
Modern pathology : an official journal of the United States and Canadian Academy of Pathology Inc, 2010Co-Authors: Jose Gaal, Francien H Van Nederveen, Paraskevi Xekouki, Esther Korpershoek, Constantine A. Stratakis, J. Aidan Carney, Evan R. Ball, Maya B. Lodish, Isaac Levy, Michael A. Den BakkerAbstract:Mutations in the tumor suppressor genes SDHB, SDHC, and SDHD (or collectively SDHx) cause the inherited paraganglioma syndromes, characterized by pheochromocytomas and paragangliomas. However, other tumors have been associated with SDHx mutations, such as gastrointestinal stromal tumors (GISTs) specifically in the context of Carney–Stratakis syndrome. Previously, we have shown that SDHB immunohistochemistry is a reliable technique for the identification of pheochromocytomas and paragangliomas caused by SDHx mutations. We hypothesized that GISTs in patients with SDHx mutations would be negative immunohistochemically for SDHB as well. Four GISTs from patients with Carney–Stratakis syndrome and six from patients with Carney triad were investigated by SDHB immunohistochemistry. Five GISTs with KIT or PDGFRA gene mutations were used as controls. In addition, SDHB immunohistochemistry was performed on 42 apparently sporadic GISTs. In cases in which the SDHB immunohistochemistry was negative, mutational analysis of SDHB, SDHC, and SDHD was performed. All GISTs from patients with Carney–Stratakis syndrome and Carney triad were negative for SDHB immunohistochemically. In one patient with Carney–Stratakis syndrome, a germline SDHB mutation was found (p.Ser92Thr). The five GISTs with a KIT or PDGFRA gene mutation were all immunohistochemically positive for SDHB. Of the 42 sporadic tumors, one GIST was SDHB-negative. Mutational analysis of this tumor did not reveal an SDHx mutation. All SDHB-negative GISTs were located in the stomach, had an epithelioid morphology, and had no KIT or PDGFRA mutations. We show that Carney–Stratakis syndrome- and Carney-triad-associated GISTs are negative by immunohistochemistry for SDHB in contrast to KIT- or PDGFRA-mutated GISTs and a majority of sporadic GISTs. We suggest that GISTs of epithelioid cell morphology are tested for SDHB immunohistochemically. In case of negative SDHB staining in GISTs, Carney–Stratakis syndrome or Carney triad should be considered and appropriate clinical surveillance should be instituted.
Anthony J Gill - One of the best experts on this subject based on the ideXlab platform.
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germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours
European Journal of Endocrinology, 2017Co-Authors: Sunita M C De Sousa, Mark J Mccabe, Tony Roscioli, Velimir Gayevskiy, Katelyn Brook, Lesley Rawlings, Hamish S Scott, Tanya J Thompson, Peter Earls, Anthony J GillAbstract:OBJECTIVE Familial pituitary tumour syndromes (FPTS) account for 5% of pituitary adenomas. Multi-gene analysis via next-generation sequencing (NGS) may unveil greater prevalence and inform clinical care. We aimed to identify germline variants in selected patients with pituitary adenomas using a targeted NGS panel. DESIGN We undertook a nationwide cross-sectional study of patients with pituitary adenomas with onset ≤40 years of age and/or other personal/family history of endocrine neoplasia. A custom NGS panel was performed on germline DNA to interrogate eight FPTS genes. Genome data were analysed via a custom bioinformatic pipeline, and validation was performed by Sanger sequencing. Multiplex ligation-dependent probe amplification (MLPA) was performed in cases with heightened suspicion for MEN1, CDKN1B and AIP mutations. The main outcomes were frequency and pathogenicity of rare variants in AIP, CDKN1B, MEN1, PRKAR1A, SDHA, SDHB, SDHC and SDHD. RESULTS Forty-four patients with pituitary tumours, 14 of whom had a personal history of other endocrine tumours and/or a family history of pituitary or other endocrine tumours, were referred from endocrine tertiary-referral centres across Australia. Eleven patients (25%) had a rare variant across the eight FPTS genes tested: AIP (p.A299V, p.R106C, p.F269F, p.R304X, p.K156K, p.R271W), MEN1 (p.R176Q), SDHB (p.A2V, p.S8S), SDHC (p.E110Q) and SDHD (p.G12S), with two patients harbouring dual variants. Variants were classified as pathogenic or of uncertain significance in 9/44 patients (20%). No deletions/duplications were identified in MEN1, CDKN1B or AIP. CONCLUSIONS A high yield of rare variants in genes implicated in FPTS can be found in selected patients using an NGS panel. It may also identify individuals harbouring more than one rare variant.
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SDHB sdha immunohistochemistry in pheochromocytomas and paragangliomas a multicenter interobserver variation analysis using virtual microscopy a multinational study of the european network for the study of adrenal tumors ens t
Modern Pathology, 2015Co-Authors: Thomas G Papathomas, Anthony J Gill, Xavier Matiasguiu, Lindsey Oudijk, Alexandre Persu, Francien H Van Nederveen, Arthur S Tischler, Frederique Tissier, Marco Volante, Marcel SmidAbstract:Despite the established role of SDHB/SDHA immunohistochemistry as a valuable tool to identify patients at risk for familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, the reproducibility of the assessment methods has not as yet been determined. The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web-based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non-SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis. Substantial agreement among all the reviewers was observed either with a two-tiered classification (SDHB κ=0.7338; SDHA κ=0.6707) or a three-tiered classification approach (SDHB κ=0.6543; SDHA κ=0.7516). Consensus was achieved in 315 cases (89.74%) for SDHB immunohistochemistry and in 348 cases (99.15%) for SDHA immunohistochemistry. Among the concordant cases, 62 of 69 (~90%) SDHB-/C-/D-/AF2-mutated cases displayed SDHB immunonegativity and SDHA immunopositivity, 3 of 4 (75%) with SDHA mutations showed loss of SDHA/SDHB protein expression, whereas 98 of 105 (93%) non-SDH-x-mutated counterparts demonstrated retention of SDHA/SDHB protein expression. Two SDHD-mutated extra-adrenal paragangliomas were scored as SDHB immunopositive, whereas 9 of 128 (7%) tumors without identified SDH-x mutations, 6 of 37 (~16%) VHL-mutated, as well as 1 of 21 (~5%) NF1-mutated tumors were evaluated as SDHB immunonegative. Although 14 out of those 16 SDHB-immunonegative cases were nonmetastatic, an overall significant correlation between SDHB immunonegativity and malignancy was observed (P=0.00019). We conclude that SDHB/SDHA immunohistochemistry is a reliable tool to identify patients with SDH-x mutations with an additional value in the assessment of genetic variants of unknown significance. If SDH molecular genetic analysis fails to detect a mutation in SDHB-immunonegative tumor, SDHC promoter methylation and/or VHL/NF1 testing with the use of targeted next-generation sequencing is advisable.
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Use of SDHB immunohistochemistry to identify germline mutations of SDH genes
Hereditary Cancer in Clinical Practice, 2012Co-Authors: Anthony J GillAbstract:Pheochromocytomas and paragangliomas occur sporadically but are commonly associated with the von Hippel Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1) and germline mutations of succinate dehydrogenase B (SDHB), C (SDHC) or D (SDHD). It is therefore recommended that genetic testing be considered if not performed in all cases of even apparently sporadic pheochromocytomas or paragangliomas. Recently it has been demonstrated that immunohistochemistry (IHC) for SDHB is negative in all SDH mutated paragangliomas regardless of whether the B,C or D subunit is involved [1,2]. Furthermore some clearly syndromic paragangliomas without known genetic mutation (including but not limited to those which occur in the Carney Triad) are identified by negative staining for SDHB [3]. Although historically the renal tumours occurring in the setting of SDHB mutation were usually classified as conventional clear cell carcinoma or oncocytoma, they actually display a unique morphology (unrecognized until know) and which can be confirmed by immunohistochemistry. The GISTs occurring in SDH mutation and Carney Triad are also unique and demonstrate quite a different morphology, natural history and molecular pathogenesis compared to other GISTs occurring in adults (but similar to most GISTs occurring in childhood). We call this unique subtype of GIST the type 2 GIST. Briefly type 2 GISTs arise in the stomach, show an epithelioid morphology, are often multifocal, commonly show lymph node metastasis, are wild type for KIT and PDGFR, have a prognosis not predicted by size and mitotic rate, never respond to imatinib but demonstrate an indolent growth despite the presence of frequent metastases [3,5]. We recommend that all paragangliomas, GISTs which potentially display type 2 morphological or clinical features and renal carcinomas which display the unique morphology we described should undergo immunohistochemistry for SDHB. Negative staining for SDHB indicates an abnormality of the mitochondrial complex 2 and is an absolute indication for formal genetic testing. We perform and interpret SDHB immunohistochemistry of archived formalin fixed paraffin embedded tissue in a manner analogous to MSI testing in colon cancer. In the setting of paraganglioma or renal carcinoma negative staining almost always indicates germline SDHB,SDHC or SDHD mutation (greater than 90% chance) but may indicate Carney Triad. In the setting of GIST, Carney Triad is more likely, but SDHB, SDHC or SDHD mutation accounts for at least 25% of type 2 GIST. Table 1 Syndromes associated with paraganglioma and pheochromocytoma The mitochondrial complex 2 links the Krebs cycle and the electron transport chain and is illustrated below: Figure 1
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immunohistochemistry for SDHB triages genetic testing of SDHB sdhc and sdhd in paraganglioma pheochromocytoma syndromes
Human Pathology, 2010Co-Authors: Anthony J Gill, Diana E Benn, Angela Chou, Adele Clarkson, Anita Muljono, Goswin Y Meyerrochow, Anne Louise Richardson, Stan B SidhuAbstract:Up to 30% of pheochromocytomas and paragangliomas are associated with germline RET, Von Hippel-Lindau (VHL), neurofibromatosis type I (NF1), and succinate dehydrogenase subunits (SDHB, SDHC, and SDHD) mutations. Genetic testing allows familial counseling and identifies subjects at high risk of malignancy (SDHB mutations) or significant multiorgan disease (RET, VHL, or NF1). However, conventional genetic testing for all loci is burdensome and costly. We performed immunohistochemistry for SDHB on 58 tumors with known SDH mutation status. We defined positive as granular cytoplasmic staining (a mitochondrial pattern), weak diffuse as a cytoplasmic blush lacking definite granularity, and negative as completely absent staining in the presence of an internal positive control. All 12 SDH mutated tumors (6 SDHB, 5 SDHD, and 1 SDHC) showed weak diffuse or negative staining. Nine of 10 tumors with known mutations of VHL, RET, or NF1 showed positive staining. One VHL associated tumor showed weak diffuse staining. Of 36 tumors without germline mutations, 34 showed positive staining. One paraganglioma with no known SDH mutation but clinical features suggesting familial disease was negative, and one showed weak diffuse staining. We also performed immunohistochemistry for SDHB on 143 consecutive unselected tumors of which 21 were weak diffuse or negative. As SDH mutations are virtually always germline, we conclude that approximately 15% of all pheochromocytomas or paragangliomas are associated with germline SDH mutation and that immunohistochemistry can be used to triage genetic testing. Completely absent staining is more commonly found with SDHB mutation, whereas weak diffuse staining often occurs with SDHD mutation.
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The Role of Immunohistochemistry and Molecular Analysis of Succinate Dehydrogenase in the Diagnosis of Endocrine and Non-Endocrine Tumors and Related Syndromes
Endocrine Pathology, 2019Co-Authors: Lindsey Oudijk, Jose Gaal, Ronald R. KrijgerAbstract:Succinate dehydrogenase (SDH) is an enzyme complex, composed of four protein subunits, that plays a role in both the citric acid cycle and the electron transport chain. The genes for SDHA, SDHB, SDHC, and SDHD are located in the nuclear DNA, and mutations in these genes have initially been described in paragangliomas (PGL) and pheochromocytomas (PCC), which are relatively rare tumors derived from the autonomic nervous system and the adrenal medulla, respectively. Patients with SDH mutations, that are almost exclusively in the germline, are frequently affected by multiple PGL and/or PCC. In addition, other tumors have been associated with SDH mutations as well, including gastrointestinal stromal tumors, SDH-deficient renal cell carcinoma, and pituitary adenomas. Immunohistochemistry for SDHB and SDHA has been shown to be a valuable additional tool in the histopathological analysis of these tumors, and can be considered as a surrogate marker for molecular analysis. In addition, SDHB immunohistochemistry is relevant in the decision-making whether a genetic sequence variant represents a pathogenic mutation or not. In this review, we highlight the current knowledge of the physiologic and pathologic role of the SDH enzyme complex and its involvement in endocrine and non-endocrine tumors, with an emphasis on the applicability of immunohistochemistry.
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non pheochromocytoma pcc paraganglioma pgl tumors in patients with succinate dehydrogenase related pcc pgl syndromes a clinicopathological and molecular analysis
European Journal of Endocrinology, 2014Co-Authors: Thomas G Papathomas, Jeanpierre Bayley, Lindsey Oudijk, Jose Gaal, Esther Korpershoek, Eleonora P M Corssmit, Ketil Heimdal, Hans Morreau, Marieke F Van Dooren, Konstantinos PapaspyrouAbstract:textabstractObjective: 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.
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SDHB immunohistochemistry a useful tool in the diagnosis of carney stratakis and carney triad gastrointestinal stromal tumors
Modern Pathology, 2011Co-Authors: Jose Gaal, Francien H Van Nederveen, Paraskevi Xekouki, Esther Korpershoek, Constantine A. Stratakis, Evan R. Ball, Maya B. Lodish, Isaac Levy, Aidan J Carney, Michael Den A BakkerAbstract:Mutations in the tumor suppressor genes SDHB, SDHC, and SDHD (or collectively SDHx) cause the inherited paraganglioma syndromes, characterized by pheochromocytomas and paragangliomas. However, other tumors have been associated with SDHx mutations, such as gastrointestinal stromal tumors (GISTs) specifically in the context of Carney–Stratakis syndrome. Previously, we have shown that SDHB immunohistochemistry is a reliable technique for the identification of pheochromocytomas and paragangliomas caused by SDHx mutations. We hypothesized that GISTs in patients with SDHx mutations would be negative immunohistochemically for SDHB as well. Four GISTs from patients with Carney–Stratakis syndrome and six from patients with Carney triad were investigated by SDHB immunohistochemistry. Five GISTs with KIT or PDGFRA gene mutations were used as controls. In addition, SDHB immunohistochemistry was performed on 42 apparently sporadic GISTs. In cases in which the SDHB immunohistochemistry was negative, mutational analysis of SDHB, SDHC, and SDHD was performed. All GISTs from patients with Carney–Stratakis syndrome and Carney triad were negative for SDHB immunohistochemically. In one patient with Carney–Stratakis syndrome, a germline SDHB mutation was found (p.Ser92Thr). The five GISTs with a KIT or PDGFRA gene mutation were all immunohistochemically positive for SDHB. Of the 42 sporadic tumors, one GIST was SDHB-negative. Mutational analysis of this tumor did not reveal an SDHx mutation. All SDHB-negative GISTs were located in the stomach, had an epithelioid morphology, and had no KIT or PDGFRA mutations. We show that Carney–Stratakis syndrome- and Carney-triad-associated GISTs are negative by immunohistochemistry for SDHB in contrast to KIT- or PDGFRA-mutated GISTs and a majority of sporadic GISTs. We suggest that GISTs of epithelioid cell morphology are tested for SDHB immunohistochemically. In case of negative SDHB staining in GISTs, Carney–Stratakis syndrome or Carney triad should be considered and appropriate clinical surveillance should be instituted.
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SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinal stromal tumors
Modern pathology : an official journal of the United States and Canadian Academy of Pathology Inc, 2010Co-Authors: Jose Gaal, Francien H Van Nederveen, Paraskevi Xekouki, Esther Korpershoek, Constantine A. Stratakis, J. Aidan Carney, Evan R. Ball, Maya B. Lodish, Isaac Levy, Michael A. Den BakkerAbstract:Mutations in the tumor suppressor genes SDHB, SDHC, and SDHD (or collectively SDHx) cause the inherited paraganglioma syndromes, characterized by pheochromocytomas and paragangliomas. However, other tumors have been associated with SDHx mutations, such as gastrointestinal stromal tumors (GISTs) specifically in the context of Carney–Stratakis syndrome. Previously, we have shown that SDHB immunohistochemistry is a reliable technique for the identification of pheochromocytomas and paragangliomas caused by SDHx mutations. We hypothesized that GISTs in patients with SDHx mutations would be negative immunohistochemically for SDHB as well. Four GISTs from patients with Carney–Stratakis syndrome and six from patients with Carney triad were investigated by SDHB immunohistochemistry. Five GISTs with KIT or PDGFRA gene mutations were used as controls. In addition, SDHB immunohistochemistry was performed on 42 apparently sporadic GISTs. In cases in which the SDHB immunohistochemistry was negative, mutational analysis of SDHB, SDHC, and SDHD was performed. All GISTs from patients with Carney–Stratakis syndrome and Carney triad were negative for SDHB immunohistochemically. In one patient with Carney–Stratakis syndrome, a germline SDHB mutation was found (p.Ser92Thr). The five GISTs with a KIT or PDGFRA gene mutation were all immunohistochemically positive for SDHB. Of the 42 sporadic tumors, one GIST was SDHB-negative. Mutational analysis of this tumor did not reveal an SDHx mutation. All SDHB-negative GISTs were located in the stomach, had an epithelioid morphology, and had no KIT or PDGFRA mutations. We show that Carney–Stratakis syndrome- and Carney-triad-associated GISTs are negative by immunohistochemistry for SDHB in contrast to KIT- or PDGFRA-mutated GISTs and a majority of sporadic GISTs. We suggest that GISTs of epithelioid cell morphology are tested for SDHB immunohistochemically. In case of negative SDHB staining in GISTs, Carney–Stratakis syndrome or Carney triad should be considered and appropriate clinical surveillance should be instituted.
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Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2010Co-Authors: Nidia Y. Cerecer-gil, Jose Gaal, Luis E. Figuera, Francisco J. Llamas, Mauricio Lara, José G. Escamilla, Ruben Ramos, Gerardo Estrada, A. Karim Hussain, Esther KorpershoekAbstract:Purpose: Paragangliomas of the head and neck are neuroendocrine tumors and are associated with germ line mutations of the tricarboxylic acid cycle–related genes SDHB, SDHC, SDHD , and SDHAF2 . Hypoxia is important in most solid tumors, and was directly implicated in tumorigenesis over 40 years ago when it was shown that dwelling at high altitudes increases the incidence of carotid body hyperplasia and paragangliomas. Although recent research has now elucidated several pathways of hypoxia in paragangliomas, nothing is currently known of the genetics or of gene-environment interactions in high-altitude paraganglioma. We postulated that SDH mutations might play a role in these tumors. Experimental Design: Patients from a Mexican family, originating and resident in Guadalajara, were tested for mutations of SDHD , and subsequently, for mutations of SDHB followed by immunohistochemical confirmation of SDHB loss. Results: Two patients, born and resident at altitudes of between 1,560 and 2,240 m, were found to have head and neck paragangliomas, including a remarkably aggressive recurrent tumor. Mutation analysis identified a pathogenic missense mutation in exon 7 of SDHB , c.689G>A, p.Arg230His, and loss of the SDHB protein was confirmed by immunohistochemistry. Conclusions: This is the first report of a SDH gene mutation in paraganglioma at high altitude. A rapidly recurrent head and neck paraganglioma is a very rare finding in an SDH mutation carrier, suggesting a gene-environment interaction. Neither patient showed evidence of sympathetic paraganglioma. Clin Cancer Res; 16(16); 4148–54. ©2010 AACR.
