An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis

Nederveen, Francien H. van; Gaal, José; Favier, Judith; Korpershoek, Esther; Oldenburg, Rogier A.; Bruyn, Elly M C A de; Sleddens, Hein F.B.M.; Derkx, Pieter; Rivière, Julie; Dannenberg, Hilde; Petri, Bart‐Jeroen; Komminoth, Paul; Pacák, Karel; Hop, Wim C. J.; Pollard, Patrick J.; Mannelli, Massimo; Bayley, Jean‐Pierre; Perren, Aurel; Niemann, Stephan; Verhofstad, A.A.J.; Bruïne, Adriaan P. de; Maher, Eamonn R.; Tissier, Frédérique; Méatchi, Tchao; Badoual, Cécile; Bertherat, Jérôme; Amar, Laurence; Alataki, Despoina; Marck, Eric Van; Ferraú, Francesco; François, Jerney; Herder, Wouter W. de; Peeters, Mark-Paul F. M. Vrancken; Linge, Anne van; Lenders, Jacques W.M.; Gimenez-Roqueplo, Anne-Paule; Krijger, Ronald R. de; Dinjens, Winand N.M.

doi:10.1016/s1470-2045(09)70164-0

Cited by 476 publications

(420 citation statements)

References 29 publications

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“…In addition, the mutations were associated with the immunohistochemical results of the SDHA and SDHB staining because this technique has been proven to reliably predict the presence of an SDH mutation: A negative SDHB staining is predictive of the presence of a mutation in any SDH subunit, with a sensitivity of 100% and a specificity of 84%, whereas a negative SDHA staining predicts an SDHA mutation with a sensitivity of 100% and a specificity of 97%. 34,35 The IHC results were available for 145 previously reported mutations. In the vast majority (134, or 92%), the IHC pattern was consistent with the prediction obtained by bioinformatics (Supplementary Table S1 online).…”

Section: In Silico Analysis Of the Functional Impact Of Sdh Mutationsmentioning

confidence: 99%

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

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Papathomas

Krol

et al. 2015

Genetics in Medicine

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The tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is a heterotetramer protein complex consisting of four subunits encoded by nuclear genes. These include SDHA and SDHB, which form the catalytic domain, and SDHC and SDHD, which anchor the complex to the inner mitochondrial membrane. 1 The assembly factors, SDHAF1 and SDHAF2, ensure both structural and functional integrity of the complex. 2,3 SDH, also called mitochondrial complex II, is the only enzyme involved in both the electron transport chain and the TCA cycle, where it catalyzes the oxidation of succinate to fumarate. 1 The TCA cycle is central to the metabolism of sugars, lipids, and amino acids and is a major source of adenosine triphosphate in cells. In addition, the cycle also seems to be involved in tumorigenesis; enzymes of the TCA cycle are involved in the pathogenesis of several tumor types. SDH mutations have been involved in the etiopathogeny of pheochromocytomas (PCCs), paragangliomas (PGLs), gastrointestinal stromal tumors (GISTs), renal-cell carcinomas (RCCs), and pituitary adenomas (PAs). 1,2,[4][5][6][7][8][9] In addition, mutations in fumarate hydratase (FH), another member of the TCA cycle and which catalyzes the hydration of fumarate to malate, predispose to tumor formation, including RCCs, cutaneous and uterine leiomyomas, and PCCs/PGLs. 10,11 Finally, isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate, is frequently mutated in specific types of cartilaginous tumors, hematological malignancies, and gliomas. 12-14 The currently known mechanisms underlying tumorigenesis linked to defects in the TCA cycle are well reviewed. 15,16 Defects in the SDH, FH, and IDH genes inhibit prolyl hydroxylases, leading to decreased hydroxylation of hypoxia-inducible factor-α. This results in activation of the hypoxia pathway, which supports tumor formation by activating angiogenesis, glucose metabolism, cell motility, and cell survival. Furthermore, defects in these enzymes lead to epigenetic alterations through an accumulation of oncometabolites inhibiting α-ketoglutarate-dependent dioxygenases, which are involved in DNA and histone demethylation. In addition to SDH-associated tumorigenesis, constitutional complex II deficiencies caused by SDHA, SDHB, SDHD, and SDHAF1 mutations may also lead to Leigh syndrome, infantile leukodystrophies, and cardiomyopathy. 3,[17][18][19] In the current review, our aim is to report all currently known SDH mutations and define their nature and spectrum in SDHrelated tumors, including PCCs/PGLs, GISTs, RCCs, and PAs, as well as in other unusual tumors arising in SDH mutation carriers. We performed bioinformatics analysis using SIFT, Polyphen2, and Mutation Assessor and compared the results with those of SDHA/SDHB immunohistochemistry (IHC) to predict the functional impact of nonsynonymous mutations. Finally, we explored and report here the nature of the second hit in all tumors arising in the SDH deficiency setting. The tricarboxylic acid, or Krebs, cycle is cent...

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Section: In Silico Analysis Of the Functional Impact Of Sdh Mutationsmentioning

confidence: 99%

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Evenepoel

Papathomas

Krol

et al. 2015

Genetics in Medicine

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“…Genetic testing algorithms based on clinical features (that is, tumour localization, malignancy and syndromic characteristics), biochemical profile (that is, types of catecholamines secreted by the tumour) or immunohistochemistry pattern have been developed to aid prioritizing genetic testing of a single or a few PPGLs susceptibility genes [5][6][7][8][9] . Although this approach is helpful for patients in whom a pathogenic driver mutation is identified promptly, it can be cumbersome when this quick identification does not happen, as the analysis must be extended to the remaining susceptibility genes.…”

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Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

et al. 2016

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Phaeochromocytomas and paragangliomas (PPGLs) are neural-crest-derived tumours of the sympathetic or parasympathetic nervous system that are often inherited and are genetically heterogeneous. Genetic testing is recommended for patients with these tumours and for family members of patients with hereditary forms of PPGLs. Due to the large number of susceptibility genes implicated in the diagnosis of inherited PPGLs, next-generation sequencing (NGS) technology is ideally suited for carrying out genetic screening of these individuals. This Consensus Statement, formulated by a study group comprised of experts in the field, proposes specific recommendations for the use of diagnostic NGS in hereditary PPGLs. In brief, the study group recommends target gene panels for screening of germ line DNA, technical adaptations to address different modes of disease transmission, orthogonal validation of NGS findings, standardized classification of variant pathogenicity and uniform reporting of the findings. The use of supplementary assays, to aid in the interpretation of the results, and sequencing of tumour DNA, for identification of somatic mutations, is encouraged. In addition, the study group launches an initiative to develop a gene-centric curated database of PPGL variants, with annual re-evaluation of variants of unknown significance by an expert group for purposes of reclassification and clinical guidance.

Funding Agencies|Cancer Prevention and Research Institute of Texas (CPRIT) [RP101202, RP57154]; Department of Defense [CDMRP W81XWH-12-1-0508]; Voelcker Fund; National Institutes of Health (NIH)s National Center for Research Resources; National Center for Advancing Translational Sciences [8UL1TR000149]; INSERM; French National Cancer Institute (INCA); Direction Generale de lOffre de Soins (DGOS); INCA [INCA-DGOS_8663]; European Union [633983]; Brazilian National Council for Scientific and Technological Development (CNPq); Cancer Research for PErsonalized Medicine (CARPEM); ERC Advanced Researcher Award

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“…14,[27][28][29] A similar genotype/immunophenotype correlation has also been noted in paragangliomas, with mutations in SDHB, SDHC, or SDHD, leading to loss of SDHB expression. 13,30 Recently, loss of expression of both SDHA and SDHB by immunohistochemistry in paragangliomas was shown to correlate specifically with mutations in the SDHA gene. 31 In this study, we sought to determine whether immunohistochemistry for SDHA in SDHdeficient GISTs could similarly predict loss-offunction mutations in SDHA.…”

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Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

et al. 2013

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Gastrointestinal stromal tumors (GISTs) are usually driven by mutations in KIT or PDGFRA, although 15% of GISTs in adults and 490% in children lack such mutations. The majority of gastric KIT/PDGFRA wild-type GISTs show distinctive morphological and clinical features and loss of expression of succinate dehydrogenase (SDH) B. Only a small subset of SDHB-deficient GISTs carries loss-of-function mutations in SDHB, SDHC, or SDHD. Because of the complexity of its locus (15 exons) and the presence of three pseudogenes, SDHA is rarely analyzed. Recently, mutations in SDHA were shown to lead to loss of expression of SDHA in a small group of paragangliomas. We sought to determine whether immunohistochemistry for SDHA could identify GISTs with SDHA mutations. Tumors (n ¼ 33) with pathological features of SDH-deficient GIST were analyzed for expression of SDHA and SDHB by immunohistochemistry, and SDHA exons were sequenced from tumors lacking SDHA expression. Exons harboring somatic mutations were examined in DNA from corresponding normal tissue. All 33 tumors showed loss of SDHB expression. A total of 9 out of 33 (27%) tumors also lacked expression of SDHA. SDHA-deficient GISTs affected five men and four women (median age 38 years). SDHA expression was intact in the 24 remaining tumors, including those with known SDHB (n ¼ 3) or SDHC (n ¼ 2) mutations. Nonsense (n ¼ 8) or missense (n ¼ 1) mutations in SDHA were identified in all SDHA-deficient tumors. Heterozygous mutations were also found in DNA from normal tissues from six patients with available material. Somatic loss of the second allele has been found in seven tumors, five by loss of heterozygosity, one by a 13-bp deletion, and one by a missense mutation. Loss of SDHA expression in GIST reliably predicts the presence of SDHA mutations, which represent a relatively common cause of SDH-deficient GIST in adults. Immunohistochemistry for SDHA can be used to select patients for SDHA-specific genetic testing.

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An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis

Cited by 476 publications

References 29 publications

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

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