Renal Tumors Associated With Germline SDHB Mutation Show Distinctive Morphology

Gill, Anthony J.; Pachter, Nicholas; Chou, Angela; Young, Brian J.; Clarkson, Adele; Tucker, Katherine; Winship, Ingrid; Earls, Peter; Benn, Diana E.; Robinson, Bruce G.; Fleming, Stewart; Clifton‐Bligh, Roderick

doi:10.1097/pas.0b013e318227e7f4

Cited by 168 publications

(165 citation statements)

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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%

“…The clinical and pathological features of six of these SDH-deficient GISTs and the three neurofibromatosis 1 syndrome-related GISTs have been previously published. 3,14 The control group comprised 40 consecutive and unselected upper gastrointestinal (gastric and duodenal) GISTs diagnosed at Royal North Shore Hospital from January 1999 to June 2004. This control group included selected patients (upper gastrointestinal GISTs cases) from a larger control cohort on which the SDHB staining has been previously described.…”

Section: Patientsmentioning

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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Section: Genetic Analysismentioning

confidence: 99%

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Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

et al. 2012

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“…13,15 The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. 16 Germline mutations in these genes have been identified in patients with paraganglioma, [17][18][19][20][21][22] renal cell carcinoma, 23,24 and GIST, 11,12 as well as syndromes of multiple tumor types. 11,13 In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA.…”

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confidence: 99%

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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“…Several other neoplasms have been reported in SDHx mutation carriers including papillary thyroid carcinoma (PTC), medullary thyroid carcinoma, pancreatic neuroendocrine tumor, adrenal cortical adenoma, neuroblastoma (NBL), ganglioneuroma (GN), adenomatoid tumor of the adrenal gland, melanoma, lung cancer, breast carcinoma, oesophageal cancer, rectal and ovarian carcinomas, uterine adenocarcinoma, uterine leiomyoma, testicular seminoma, bladder cancer, meningioma, oligodendroglioma, cecal polyps, and hematolymphoid malignancies (7,8,9,10,11,12,13,14,15,16,17,18,19).…”

Section: Introductionmentioning

confidence: 99%

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis

Papathomas

Gaal

Corssmit

et al. 2014

European Journal of Endocrinology

119

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Objective: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated. Design and methods: Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC. Printed in Great BritainPublished by Bioscientifica Ltd.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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Renal Tumors Associated With Germline SDHB Mutation Show Distinctive Morphology

Cited by 168 publications

References 21 publications

Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

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

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis

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