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Anthony J Gill - One of the best experts on this subject based on the ideXlab platform.

  • Bayesian approach to determining penetrance of pathogenic SDH variants.
    Journal of medical genetics, 2018
    Co-Authors: Diana E Benn, Katrina A Andrews, Trisha Dwight, Ying Zhu, Mathilda Wilding, Emma L. Duncan, Richard W. Tothill, John Burgess, Ashley Crook, Anthony J Gill
    Abstract:

    Background Until recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional to their penetrance for disease. We tested this hypothesis using data from two cohorts for succinate dehydrogenase subunits A, B and C (SDHA–C) genetic variants associated with hereditary pheochromocytoma/paraganglioma (PC/PGL). Methods Two cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic SDHA–C variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas). Results Pathogenic SDHA–C variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 different pathogenic variants from both cohorts (seven in SDHA, 75 in SDHB and 12 in SDHC), 13 are reported in ExAC (two in SDHA, nine in SDHB and two in SDHC) accounting for 21% of subjects with SDHA–C variants. Combining data from both cohorts, estimated lifetime disease penetrance was 22.0% (95% CI 15.2% to 30.9%) for SDHB variants, 8.3% (95% CI 3.5% to 18.5%) for SDHC variants and 1.7% (95% CI 0.8% to 3.8%) for SDHA variants. Conclusion Pathogenic variants in SDHB are more penetrant than those in SDHC and SDHA. Our findings have important implications for counselling and surveillance of subjects carrying these pathogenic variants.

  • succinate dehydrogenase sdh deficient neoplasia
    Histopathology, 2018
    Co-Authors: Anthony J Gill
    Abstract:

    The succinate dehydrogenase (SDH) complex is a key respiratory enzyme composed of four subunits: SDHA, SDHB, SDHC and SDHD. Remarkably, immunohistochemistry for SDHB becomes negative whenever there is bi-alleic inactivation of any component of SDH, which is very rare in the absence of syndromic disease. Therefore, loss of SDHB immunohistochemistry serves as a marker of syndromic disease, usually germline mutation of one of the SDH subunits. Tumours which show loss of SDHB expression are termed succinate dehydrogenase-deficient. In addition to loss of SDHB, tumours associated with SDHA mutation also show loss of SDHA expression. Fifteen per cent of pheochromocytoma and paraganglioma (PHEO/PGL) are associated with germline SDH mutation, and therefore SDH-deficient. We recommend screening SDHB immunohistochemistry for all PHEO/PGL. SDH-deficient gastrointestinal stromal tumours (GISTs) show distinctive features, including absent KIT proto-oncogene receptor tyrosine kinase/platelet-derived growth factor receptor A (KIT/PDGFRA) mutations [but positive staining for cKIT and DOG1], virtually exclusive gastric location, lobulated growth, multi-focality, a prognosis not predicted by size and mitotic rate, frequent metastasis to lymph nodes and primary resistance to imatinib therapy. Thirty per cent are associated with SDHA germline mutation and 50% are associated with SDHC epimutation (post-zygotic promoter hypermethylation) - the hallmark of the syndromic but non-hereditary Carney triad (SDH- deficient GIST, SDH-deficient paraganglioma and pulmonary chondroma). SDH-deficient renal carcinoma is newly recognized under the World Health Organization (WHO) 2016 classification and shows vacuolated eosinophilic cytoplasmic and cytoplasmic inclusions. It is particularly associated with SDHB mutation, although SDHC and SDHA mutation occur. SDH-deficient pituitary adenomas are recognized, but appear to be the least common SDH-deficient neoplasm.

  • germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours
    European Journal of Endocrinology, 2017
    Co-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 Gill
    Abstract:

    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.

  • 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, 2015
    Co-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 Smid
    Abstract:

    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.

  • succinate dehydrogenase deficiency is rare in pituitary adenomas
    The American Journal of Surgical Pathology, 2014
    Co-Authors: Anthony J Gill, Diana E Benn, Angela Chou, Adele Clarkson, Bruce G Robinson, Roderick J Cliftonbligh, Christopher W Toon, Loretta Sioson, Ingrid Winship, Trisha Dwight
    Abstract:

    The reported prevalence of pituitary adenomas is up to 1 in 1000.1 At least 5% are hereditary, and there are clear associations with multiple endocrine neoplasia type 1 (MEN1, associated with MEN1 mutation), familial isolated pituitary adenoma (often associated with AIP mutation), Carney complex (often associated with PRKAR1A mutation), and MEN4 (associated with CDKN1B mutation).2,3 However, there remain cases of hereditary pituitary adenoma for which no clear syndromic or genetic cause has been identified. The succinate dehydrogenase (SDH) genes SDHA, SDHB, SDHC, and SDHD encode the protein subunits of the mitochondrial complex II, a key respiratory enzyme that links the Krebs cycle and the electron transport chain.4 These genes also function as tumor-suppressor genes, and germline SDH mutations are associated with a tumor syndrome characterized by pheochromocytoma/paraganglioma,5 a unique subtype of gastrointestinal stromal tumor (GIST) known as SDH-deficient GIST6 and a distinctive type of renal carcinoma.7 It is noteworthy that loss of immunohistochemical (IHC) staining for SDHB has been consistently identified in pheochromocytomas/paragangliomas,8,9 GISTs,6,10–14 and renal carcinomas7,15 associated with SDH mutation regardless of which SDH subunit is mutated. In addition to loss of SDHB staining, negative staining for SDHA also occurs in pheochromocytomas/paragangliomas16 and GISTs17,18 associated with SDHA mutation. To date, SDHA mutation has not been reported in association in with renal carcinoma. Tumors that show negative staining for SDHB are known as succinate dehydrogenase deficient, and IHC for SDHB and SDHA is used routinely to screen patients presenting with compatible tumors for germline SDH mutation.4 There is now emerging evidence that pituitary adenomas may also be associated with SDH mutation. Briefly, 35 cases of coexistent pheochromocytoma/paraganglioma and pituitary adenoma in individuals or kindreds have been reported,3,19–26 and second-hit inactivation has been demonstrated by either loss of heterozygosity19 or acquired mutation23 in 2 pituitary adenomas arising in the setting of germline SDH mutation. However, to date, the evidence linking SDH mutation and pituitary neoplasia has been based on case reports, and the incidence and clinical significance of SDH mutation in pituitary adenomas is unknown. In this study, we sought to estimate the incidence and clinicopathologic associations of SDH mutation in pituitary adenomas.

Jeanpierre Bayley - One of the best experts on this subject based on the ideXlab platform.

  • variant type is associated with disease characteristics in sdhb sdhc and SDHD linked phaeochromocytoma paraganglioma
    Journal of Medical Genetics, 2020
    Co-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 Corssmit
    Abstract:

    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.

  • simple and rapid characterization of novel large germline deletions in sdhb sdhc and SDHD related paraganglioma
    Clinical Genetics, 2017
    Co-Authors: Attje S. Hoekstra, Hartmut P. H. Neumann, Peter Devilee, Carli M J Tops, B Van Den Ende, X P Julia, L Van Breemen, K Scheurwater, A Malinoc, Jeanpierre Bayley
    Abstract:

    Germline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with hereditary paraganglioma and pheochromocytoma. Although most mutations in SDHB, SDHC and SDHD are intraexonic variants, large germline deletions may represent up to 10% of all variants but are rarely characterized at the DNA sequence level. Additional phenotypic effects resulting from deletions that affect neighboring genes are also not understood. We performed multiplex ligation-dependent probe amplification, followed by a simple long-range PCR 'chromosome walking' protocol to characterize breakpoints in 20 SDHx-linked paraganglioma-pheochromocytoma patients. Breakpoints were confirmed by conventional PCR and Sanger sequencing. Heterozygous germline deletions of up to 104 kb in size were identified in SDHB, SDHC, SDHD and flanking genes in 20 paraganglioma-pheochromocytoma patients. The exact breakpoint could be determined in 16 paraganglioma-pheochromocytoma patients of which 15 were novel deletions. In six patients proximal genes were also deleted, including PADI2, MFAP2, ATP13A2 (PARK9), CFAP126, TIMM8B and C11orf57. These genes were either partially or completely deleted, but did not modify the phenotype. This study increases the number of known SDHx deletions by over 50% and demonstrates that a significant proportion of large gene deletions can be resolved at the nucleotide level using a simple and rapid method.

  • succinate dehydrogenase sdh deficient pancreatic neuroendocrine tumor expands the sdh related tumor spectrum
    The Journal of Clinical Endocrinology and Metabolism, 2015
    Co-Authors: Nicolasine D Niemeijer, Jeanpierre Bayley, Thomas G Papathomas, Lindsey Oudijk, Esther Korpershoek, Jeroen C Jansen, Frederik J Hes, Ronald R. Krijger, Hans Morreau, Winand N.m. Dinjens
    Abstract:

    Context: Mutations in genes encoding the subunits of succinate dehydrogenase (SDH) can lead to pheochromocytoma/paraganglioma formation. However, SDH mutations have also been linked to nonparaganglionic tumors. Objective: The objective was to investigate which nonparaganglionic tumors belong to the SDH-associated tumor spectrum. Design: This was a retrospective cohort study. Setting: The setting was a tertiary referral center. Patients: Patients included all consecutive SDHA/SDHB/SDHC and SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center who were affected by non-pheochromocytoma/paraganglioma solid tumors. Main Outcome Measures: Main outcome measures were SDHA/SDHB immunohistochemistry, mutation analysis, and loss of heterozygosity analysis of the involved SDH-encoding genes. Results: Twenty-five of 35 tumors (from 26 patients) showed positive staining on SDHB and SDHA immunohistochemistry. Eight tumors showed negative staining for SDHB and positive...

  • Mutations in SDHD are the major determinants of the clinical characteristics of Dutch head and neck paraganglioma patients
    Clinical endocrinology, 2011
    Co-Authors: Erik F Hensen, Peter Devilee, Jeroen C Jansen, Eleonora P M Corssmit, Cees J Cornelisse, Carli M J Tops, Johannes A Romijn, A G L Van Der Mey, M. D. Siemers, Jeanpierre Bayley
    Abstract:

    Summary Objective  Head and neck paragangliomas (HNPGL) are associated with mutations in genes encoding subunits of succinate dehydrogenase (SDH). The aim of this study was to evaluate SDH mutations, family history and phenotypes of patients with HNPGL in the Netherlands. Design  We evaluated the clinical data and the mutation status of 236 patients referred between 1950 and 2009 to Leiden University Medical Center. Results  The large majority of the patients carried mutations in SDHD (83%), and the p.Asp92Tyr Dutch founder mutation in SDHD alone accounted for 72% of all patients with HNPGL. A mutation in SDHAF2 was found in 4%, mutations in SDHB in 3% and a mutation in SDHC was identified in a single patient (0·4%). Over 80% of patients presented with positive family history, of whom 99·5% carried a mutation in an SDH gene. SDH mutations were also found in 56% of isolated patients, chiefly in SDHD (46%), but also in SDHB (8%) and SDHC (2%). The clinical parameters of these different subgroups are discussed: including the age at diagnosis, associated pheochromocytomas, tumour multifocality and malignancy rate. Conclusion  The majority of Dutch patients with HNPGL present with a positive family history, in contrast to other European countries. The clinical characteristics of patients with HNPGL are chiefly determined by founder mutations in SDHD, the major causative gene in both familial and isolated patients with HNPGL. The high frequency of founder mutations in SDHD suggests a higher absolute prevalence of paraganglioma syndrome in the Netherlands.

  • SDHA Immunohistochemistry Detects Germline SDHA Gene Mutations in Apparently Sporadic Paragangliomas and Pheochromocytomas
    The Journal of clinical endocrinology and metabolism, 2011
    Co-Authors: Esther Korpershoek, Lindsey Oudijk, Jose Gaal, Judith Favier, Nelly Burnichon, Bram Van Gessel, Cécile Badoual, Noémie Gadessaud, Annabelle Venisse, Jeanpierre Bayley
    Abstract:

    Context: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA. Objective: In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations. Setting: This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Universite Paris Descartes in Paris (France). Methods: We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA. Results: Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a ger...

Jason L. Hornick - One of the best experts on this subject based on the ideXlab platform.

  • conventional risk stratification fails to predict progression of succinate dehydrogenase deficient gastrointestinal stromal tumors a clinicopathologic study of 76 cases
    The American Journal of Surgical Pathology, 2016
    Co-Authors: Emily F Mason, Jason L. Hornick
    Abstract:

    Gastrointestinal stromal tumors (GISTs) that lack kinase mutations often show loss of function of the succinate dehydrogenase (SDH) complex, due to germline mutation or promoter hypermethylation. SDH-deficient GISTs are exclusive to the stomach and have a multinodular architecture. It has been suggested that conventional risk stratification criteria may not predict outcome for this group of tumors, although data are limited. Here, we report the clinical, histologic, and genetic findings from a large cohort of 76 SDH-deficient GISTs diagnosed from 2005 to 2015, identified on the basis of histologic features or family history (45 female/31 male; mean age at diagnosis 32 y; range 11 to 71 y; 10 patients 50 y of age or above). Immunohistochemistry for SDHB and SDHA showed loss of SDHB in all cases and loss of SDHA in 28 (37%) tumors. Tumor size ranged from 1.9 to 22.5 cm; the primary tumor was multifocal in 29%. Mitotic rate ranged from 1 to 80 per 5 mm (median 5.5). Lymph node metastases were found at primary resection in 14 (18%) patients. Twenty-four patients (32%) had distant metastases at presentation, and 52 of 70 patients (74%) with follow-up developed distant metastases, most often to the liver, but also bone, lungs, breast, and brain. Applying conventional criteria (size and mitotic rate), 60% to 82% of patients with tumors ranging from very low risk to high risk for progressive disease developed distant metastases, regardless of the category. Carney-Stratakis syndrome and Carney triad were diagnosed in 6 and 8 patients, respectively. Of 35 patients tested, 26 harbored SDH mutations (11 SDHA, 8 SDHB, 6 SDHC, 1 SDHD). Follow-up data available for 70 patients ranged from 1 month to 39.3 years: 20 patients had no evidence of disease (mean 6.1 y), 32 were alive with metastases (mean 10.9 y), and 18 died of disease (mean 7.0 y after diagnosis). In summary, SDH-deficient GISTs account for approximately 8% of gastric GISTs and are associated with a high rate of distant metastasis, regardless of conventional risk category. Many affected patients have germline SDH mutations (most often SDHA). Identification of SDH-deficient GISTs is critical for prognostication and genetic counseling.

  • Exploring the association of succinate dehydrogenase complex mutations with lymphoid malignancies.
    Familial cancer, 2014
    Co-Authors: Raffaele Renella, Julia Carnevale, Katherine A. Schneider, Jason L. Hornick, Huma Q. Rana, Katherine A. Janeway
    Abstract:

    The succinate dehydrogenase (SDH) complex exerts a fundamental role in mitochondrial cellular respiration and mutations in its encoding genes (SDHA, SDHB, SDHC, SDHD, collectively referred to as SDHx) lead to a number of inherited endocrine cancer predisposition syndromes, including familial paraganglioma/pheochromocytoma. Recent studies suggest a possible role for the SDH complex and other mitochondrial enzymes in the pathogenesis of hematological malignancy. Our aim was to search and identify pedigrees of patients affected by germline SHDx mutations treated at our institution for endocrine and other tumors, and seek to identify cases of hematological malignancy. We also analyzed cancer genome databases for reported cases of SDHx mutations outside of endocrine neoplasms. We report of two unrelated pedigrees carrying SDHx mutations with members affected by lymphomas. Sequencing data revealed one case of chronic lymphocytic leukemia with a SDHB mutation. This novel set of observations demonstrates the need for collaborative databases of patients with endocrine cancers with SDHx mutations, and the investigation of their role in hematological (lymphoid) malignancy.

  • identification of sdha subunit a of the succinate dehydrogenase mutation in patient with carney stratakis syndrome
    American Journal of Clinical Pathology, 2013
    Co-Authors: Sharon S Zhang, John A Hart, Aliya N Husain, Andrew J Wagner, Jason L. Hornick
    Abstract:

    Carney-Stratakis syndrome, defined as the “dyad” of extra-adrenal paraganglioma and gastrointestinal stromal tumor (GIST), is caused by germline mutations in one of the succinate dehydrogenase (SDH) complex subunit genes (SDHB, SDHC, or SDHD). Herein we report the first documented mutation of SDHA in a patient with Carney-Stratakis syndrome. The …

Eamonn R Maher - One of the best experts on this subject based on the ideXlab platform.

  • Familial wild-type gastrointestinal stromal tumour in association with germline truncating variants in both SDHA and PALB2
    European Journal of Human Genetics, 2021
    Co-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 Maher
    Abstract:

    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.

  • The pressure rises: update on the genetics of phaeochromocytoma", Human molecular genetics
    2015
    Co-Authors: Eamonn R Maher, Charis Eng
    Abstract:

    Phaeochromocytomas are neoplasias of neural crest origin arising from the adrenal medulla. Extra-adrenal phaeochromocytomas occur and may be referred to as paragangliomas, although this term is also used to describe vascular head and neck tumours, which most commonly develop at the carotid bifurcation. Historically, genetic factors have been implicated in up to 10 % of phaeochromocytoma cases, but recent data suggest that germline mutations may be detected in 25 % of unselected cases. The most frequent causes of phaeochromocytoma susceptibility are von Hippel–Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), the newly delineated phaeochromocytoma–paraganglioma syndrome and, less commonly, neurofibromatosis type 1. Germline mutations in three of the succinate dehydrogenase (SDH, mitochondrial complex II) subunits (SDHD, SDHB and SDHC) cause susceptibility to head and neck paragangliomas, and may be found in 20 % of unselected patients. In addition, germline SDHD and SDHB mutations may cause phaeochromocytoma susceptibility with or without associated head and neck paragangliomas. Recent studies suggest that germline SDHD and SDHB mutations are an important cause of familial and isolated phaeochromocytoma. The mechanism by which SDH subunit mutations predispose to phaeochromocytomas has not been defined in detail, but dysregulation of hypoxia-responsive genes and impairment of mitochondria-mediated apoptosis have both been suggested

  • genetics in endocrinology the genetics of phaeochromocytoma using clinical features to guide genetic testing
    European Journal of Endocrinology, 2012
    Co-Authors: Mariam Jafri, Eamonn R Maher
    Abstract:

    : Phaeochromocytoma is a rare, usually benign, tumour predominantly managed by endocrinologists. Over the last decade, major advances have been made in understanding the molecular genetic basis of adrenal and extra-adrenal phaeochromocytoma (also referred to as adrenal phaeochromocytoma (aPCA) and extra-adrenal functional paraganglioma (eFPGL)). In contrast to the previously held belief that only 10% of cases had a genetic component, currently about one-third of all aPCA/eFPGL cases are thought to be attributable to germline mutations in at least nine genes (NF1, RET, SDHA, SDHB, SDHC, SDHD, TMEM127, MAX and VHL). Recognition of inherited cases of aPCA/eFPGL is critical for optimal patient management. Thus, the identification of a germline mutation can predict risks of malignancy, recurrent disease, associated non-chromaffin tumours and risks to other family members. Mutation carriers should be offered specific surveillance programmes (according to the relevant gene). In this review, we will describe the genetics of aPCA/eFPGL and strategies for genetic testing.

  • gene mutations in the succinate dehydrogenase subunit sdhb cause susceptibility to familial pheochromocytoma and to familial paraganglioma
    American Journal of Human Genetics, 2001
    Co-Authors: Dewi Astuti, Charis Eng, Farida Latif, Ashraf Dallol, Patricia L M Dahia, Fiona Douglas, Emad George, Filip Skoldberg, Eystein S Husebye, Eamonn R Maher
    Abstract:

    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.

Jeroen C Jansen - One of the best experts on this subject based on the ideXlab platform.

  • variant type is associated with disease characteristics in sdhb sdhc and SDHD linked phaeochromocytoma paraganglioma
    Journal of Medical Genetics, 2020
    Co-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 Corssmit
    Abstract:

    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.

  • loss of maternal chromosome 11 is a signature event in sdhaf2 SDHD and vhl related paragangliomas but less significant in sdhb related paragangliomas
    Oncotarget, 2017
    Co-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 Kunst
    Abstract:

    // 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.

  • succinate dehydrogenase sdh deficient pancreatic neuroendocrine tumor expands the sdh related tumor spectrum
    The Journal of Clinical Endocrinology and Metabolism, 2015
    Co-Authors: Nicolasine D Niemeijer, Jeanpierre Bayley, Thomas G Papathomas, Lindsey Oudijk, Esther Korpershoek, Jeroen C Jansen, Frederik J Hes, Ronald R. Krijger, Hans Morreau, Winand N.m. Dinjens
    Abstract:

    Context: Mutations in genes encoding the subunits of succinate dehydrogenase (SDH) can lead to pheochromocytoma/paraganglioma formation. However, SDH mutations have also been linked to nonparaganglionic tumors. Objective: The objective was to investigate which nonparaganglionic tumors belong to the SDH-associated tumor spectrum. Design: This was a retrospective cohort study. Setting: The setting was a tertiary referral center. Patients: Patients included all consecutive SDHA/SDHB/SDHC and SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center who were affected by non-pheochromocytoma/paraganglioma solid tumors. Main Outcome Measures: Main outcome measures were SDHA/SDHB immunohistochemistry, mutation analysis, and loss of heterozygosity analysis of the involved SDH-encoding genes. Results: Twenty-five of 35 tumors (from 26 patients) showed positive staining on SDHB and SDHA immunohistochemistry. Eight tumors showed negative staining for SDHB and positive...

  • high prevalence of founder mutations of the succinate dehydrogenase genes in the netherlands
    Clinical Genetics, 2012
    Co-Authors: Erik F Hensen, Jeroen C Jansen, Eleonora P M Corssmit, Cees J Cornelisse, N Van Duinen, Carli M J Tops, Johannes A Romijn, A H J T Vriendsd, A G L Van Der Mey, Peter Devilee
    Abstract:

    Mutations in four genes encoding subunits or cofactors of succinate dehydrogenase (SDH) cause hereditary paraganglioma and pheochromocytoma syndromes. Mutations in SDHB and SDHD are generally the most common, whereas mutations in SDHC and SDHAF2 are far less frequently observed. A total of 1045 DNA samples from Dutch paraganglioma and pheochromocytoma patients and their relatives were analyzed for mutations of SDHB, SDHC, SDHD or SDHAF2. Mutations in these genes were identified in 690 cases, 239 of which were index cases. The vast majority of mutation carriers had a mutation in SDHD (87.1%). The second most commonly affected gene was SDHAF2 (6.7%). Mutations in SDHB were found in only 5.9% of samples, whereas SDHC mutations were found in 0.3% of samples. Remarkably, 69.1% of all carriers of a mutation in an SDH gene in the Netherlands can be attributed to a single founder mutation in SDHD, c.274G>T and p.Asp92Tyr. Moreover, 88.8% of all SDH mutation carriers carry one of just six Dutch founder mutations in SDHB, SDHD and SDHAF2. The dominance of SDHD mutations is unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere. In addition, we found that most SDH mutation-related paragangliomas-pheochromocytomas in the Netherlands can be explained by only six founder mutations in SDHAF2, SDHB and SDHD. The findings underline the regional differences in the SDH mutation spectrum, differences that should be taken into account in the development of effective screening protocols. The results show the crucial role that demographic factors play in the frequency of gene mutations.

  • Mutations in SDHD are the major determinants of the clinical characteristics of Dutch head and neck paraganglioma patients
    Clinical endocrinology, 2011
    Co-Authors: Erik F Hensen, Peter Devilee, Jeroen C Jansen, Eleonora P M Corssmit, Cees J Cornelisse, Carli M J Tops, Johannes A Romijn, A G L Van Der Mey, M. D. Siemers, Jeanpierre Bayley
    Abstract:

    Summary Objective  Head and neck paragangliomas (HNPGL) are associated with mutations in genes encoding subunits of succinate dehydrogenase (SDH). The aim of this study was to evaluate SDH mutations, family history and phenotypes of patients with HNPGL in the Netherlands. Design  We evaluated the clinical data and the mutation status of 236 patients referred between 1950 and 2009 to Leiden University Medical Center. Results  The large majority of the patients carried mutations in SDHD (83%), and the p.Asp92Tyr Dutch founder mutation in SDHD alone accounted for 72% of all patients with HNPGL. A mutation in SDHAF2 was found in 4%, mutations in SDHB in 3% and a mutation in SDHC was identified in a single patient (0·4%). Over 80% of patients presented with positive family history, of whom 99·5% carried a mutation in an SDH gene. SDH mutations were also found in 56% of isolated patients, chiefly in SDHD (46%), but also in SDHB (8%) and SDHC (2%). The clinical parameters of these different subgroups are discussed: including the age at diagnosis, associated pheochromocytomas, tumour multifocality and malignancy rate. Conclusion  The majority of Dutch patients with HNPGL present with a positive family history, in contrast to other European countries. The clinical characteristics of patients with HNPGL are chiefly determined by founder mutations in SDHD, the major causative gene in both familial and isolated patients with HNPGL. The high frequency of founder mutations in SDHD suggests a higher absolute prevalence of paraganglioma syndrome in the Netherlands.