Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes

Gill, Anthony J.; Benn, Diana E.; Chou, Angela; Clarkson, Adele; Muljono, Anita; Meyer‐Rochow, Goswin Y.; Richardson, Anne; Sidhu, Stan; Robinson, Bruce G.; Clifton‐Bligh, Roderick

doi:10.1016/j.humpath.2009.12.005

Cited by 245 publications

(245 citation statements)

References 39 publications

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“…Therefore, negative staining for SDHB indicates the need for genetic testing for SDHB, SDHC, and SDHD in patients who present with pheochromocytoma-paraganglioma. 3,4 As of this writing, a single SDHB-negative renalcell carcinoma in a patient with PGL4 has been reported. 3 We performed immunohistochemical analysis to detect SDHB in renal-cell carcinoma specimens obtained from three kindreds who were subsequently shown to harbor a germline SDHB mutation (Fig.…”

Section: Renal Tumors and Hereditary Pheochromocytomaparaganglioma Symentioning

confidence: 85%

Renal Tumors and Hereditary Pheochromocytoma-Paraganglioma Syndrome Type 4

Gill¹,

Pachter²,

Clarkson³

et al. 2011

N Engl J Med

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Section: Renal Tumors and Hereditary Pheochromocytomaparaganglioma Symentioning

confidence: 85%

Renal Tumors and Hereditary Pheochromocytoma-Paraganglioma Syndrome Type 4

Gill¹,

Pachter²,

Clarkson³

et al. 2011

N Engl J Med

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“…IGF1R inhibition therefore represents a rational therapeutic target for this class of tumor, which accounts for between 5 and 7.5% of all gastric GISTs in adults 3,4 and perhaps also in the other tumors associated with mitochondrial complex 2 dysfunction, such as SDH mutated paraganglioma or the specific type of renal carcinoma associated with germline SDHB mutation. 14,16,17 …”

Section: Discussionmentioning

confidence: 99%

“…15 Immunohistochemistry SDHB immunohistochemistry was performed on formalin-fixed paraffin-embedded tissue sections using a commercially available mouse monoclonal antibody (ABCAM ab14714, clone 21A11) using previously described methods. 3,14,16,17 Briefly, in order for immunohistochemistry for SDHB to be considered negative (a significant result) we required the entire tumor to demonstrate absent granular cytoplasmic staining (that is, absent mitochondrial staining) and for there to be readily identifiable internal positive controls in non-neoplastic cells (endothelial cells). Negative staining of tumor cells in the absence of internal positive controls was considered an indeterminate result and immunohistochemistry was repeated.…”

Section: Genetic Analysismentioning

confidence: 99%

Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

et al. 2012

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Succinate dehydrogenase-deficient gastrointestinal stromal tumors (GISTs) demonstrate unique pathological and clinical features, including the absence of activating mutations of KIT and PDGFRA, and primary resistance to imatinib. They arise exclusively in the stomach and account for 5-7.5% of all adult stomach GISTs and the great majority of these tumors in childhood. Insulin-like growth factor 1 receptor (IGF1R) overexpression has been associated with wild-type and pediatric GISTs. We propose that IGF1R overexpression is a feature of succinate dehydrogenase-deficient GISTs as a group. We assessed succinate dehydrogenase complex subunit B (SDHB) and IGF1R expression by immunohistochemistry in eight known succinate dehydrogenase-deficient GISTs, three GISTs arising in the setting of neurofibromatosis type 1 syndrome and 40 unselected GISTs. Selected KIT and PDGFRA exons were amplified and sequenced from formalin-fixed paraffin-embedded tumor samples. All eight succinate dehydrogenase-deficient tumors were wild-type for KIT and PDGFRA, succinate dehydrogenase B negative and demonstrated IGF1R overexpression. The three neurofibromatosis-related tumors were succinate dehydrogenase B positive and IGF1R negative. Of the 40 unselected upper GISTs, five were wild-type for KIT and PDGFRA in the selected exons. Two of the wild-type GISTs were succinate dehydrogenase B negative and showed IGF1R overexpression and three were succinate dehydrogenase B positive and IGF1R negative. We conclude that IGF1R overexpression is a feature of succinate dehydrogenase deficient GIST as a group, rather than pediatric or wild-type GIST per se. Therefore, IGF1R inhibition represents a potential rational therapeutic approach in this recently recognized subgroup of GIST.

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“…Mutation in any of the subunits leads to instability of the complex and degradation of SDHB subunit protein. For that reason, loss of SDHB expression, as detected by immunohistochemistry (IHC), is being increasingly used as a marker for the SDHdeficient phenotype, which can subsequently be clarified by genetic studies (Gill et al 2010). SDH deficiency leads to intracellular succinate accumulation, which inhibits a broad family of enzymes that are called dioxygenases, including propyl-hydroxylases, JmjC domain-containing histone demethylases (KDMs) and the TET family of dioxygenases (Killian et al 2013, Boikos et al 2014, Wang et al 2015 (Fig.…”

Section: Sdh-deficient Gists (Sdha B C D Mutations Sdhc Epimutants)mentioning

confidence: 99%

Classification of gastrointestinal stromal tumor syndromes

Gopie

Faber

et al. 2018

Endocrine-Related Cancer

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, thought to derive from neoplastic outgrowth of the interstitial cells of Cajal. Building on recent advances in recognition, classification and diagnosis, the past two decades have seen a changing paradigm with molecular diagnostics and targeted therapies. KIT and PDGFRA mutations account for 85-90% of GIST carcinogenesis. However, the remaining 10-15% of GISTs, which until recently were called KIT/PDGFRA wild-type GISTs, have been found to have one of the several mutations, including in the SDHA, B, C, D, BRAF and NF1 genes. Though most of such GISTs are sporadic, a number of families with high incidence rates of GISTs and other associated clinical manifestations have been reported and found to harbor germline mutations in KIT, PDGFRA, SDH subunits and NF1. The goal of this review is to describe the mutations, clinical manifestations and therapeutic implications of syndromic and inherited GISTs in light of recent studies of their clinicopathologic range and pathogenesis.

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Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes

Cited by 245 publications

References 39 publications

Renal Tumors and Hereditary Pheochromocytoma-Paraganglioma Syndrome Type 4

Renal Tumors and Hereditary Pheochromocytoma-Paraganglioma Syndrome Type 4

Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

Classification of gastrointestinal stromal tumor syndromes

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