SDHD Immunohistochemistry: A New Tool to Validate<i>SDHx</i>Mutations in Pheochromocytoma/Paraganglioma

Menara, Mélanie; Oudijk, Lindsey; Badoual, Cécile; Bertherat, Jérôme; Lepoutre-Lussey, Charlotte; Amar, Laurence; Iturrioz, Xavier; Sibony, Mathilde; Zinzindohoué, F.; Krijger, Ronald R. de; Gimenez-Roqueplo, Anne-Paule; Favier, Judith

doi:10.1210/jc.2014-1870

Cited by 48 publications

(42 citation statements)

References 20 publications

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“…This suggests SDHD immunohistochemistry as a potential complementary tool to SDHB immunohistochemistry to identify SDHD-mutated patients. 62 Further adding to those rare familial cases characterized by disparity between molecular genetic aberrations of a tumor suppressor gene and retention of protein expression, 63 one papillary renal cell carcinomas arising in a patient with a germline missense SDHC mutation (c.3G4A p.M1I) and harboring somatic loss of heterozygosity of the SDHC locus paradoxically displayed SDHB immunopositivity. 36 Taken together, SDHB immunohistochemistry and SDH-x genetic analysis should be viewed as complementary tests.…”

Section: Discussionmentioning

confidence: 99%

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)

et al. 2015

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Section: Discussionmentioning

confidence: 99%

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)

et al. 2015

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“…Interestingly, in an Sdhb À/À mouse tumor model, this succinate peak is correlated with the concentrations of succinate measured in the resected tumors by GC-MS. Demonstration of SDH inactivation is currently based on in vitro analyses of tissue samples: immunohistochemical analyses of SDHB, SDHA, and SDHD expression in FFPE tissues (16,18,22), direct succinate measurements on frozen tumor samples by nuclear magnetic resonance (NMR) spectroscopy (15,19,20,23), GC-MS, or liquid chromatography mass spectroscopy (LC-MS; refs. 13,17,21).…”

Section: Discussionmentioning

confidence: 99%

“…SDHA, SDHB, and SDHD protein expression were assessed on formalin-fixed, paraffin-embedded (FFPE) tumor samples by immunohistochemistry as previously described (16,18,22) using the following antibodies: anti-SDHA (ab14715, Abcam; 1:1,000), anti-SDHB (HPA002868, Sigma-Aldrich Corp; 1:500), and anti-SDHD (HPA045727, Sigma-Aldrich Corp; 1:50).…”

Section: Immunohistochemistrymentioning

confidence: 99%

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In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

Lussey-Lepoutre

Bellucci

Morin

et al. 2016

Clinical Cancer Research

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International audiencePurpose: Germline mutations in genes encoding mitochon-drial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy. Experimental Design: A pulsed proton magnetic resonance spectroscopy (1 H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb À/À or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n ¼ 5) or not (n ¼ 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors. Results: A succinate peak was observed at 2.44 ppm by 1 H-MRS in all Sdhb À/À-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, 1 H-MRS results led to the identification of an unsus-pected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene. Conclusions: Detection of succinate by 1 H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This non-invasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. Clin Cancer Res; 22(5); 1120–9. Ó2015 AACR

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“…Negative SDHA immunostaining suggests underlying SDHA mutations. 21 The MAX IHC is negative in MAX mutations, and 2SC is positive in FH mutations. 6 These immunostaining characteristics help to prioritize genetic testing among those with the norepinephrine-secreting biochemical phenotype.…”

Section: Immunohistochemical Stainingmentioning

confidence: 97%

Genotype–phenotype Correlation in Children with Pheochromocytoma and Paraganglioma

Shah¹,

Sarathi²,

Mayilvaganan³

2016

World Journal of Endocrine Surgery

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Pheochromocytoma/paraganglioma (PPGL) have been reported to have germline mutations in more than 15 genes. PPGL diagnosed during childhood have the highest heritability (up to 80%). PPGL associated genes are classified into two clusters; cluster 1 (VHL, SDHx, EPAS1, PDH1, PDH2, FH, MDH2) and cluster 2 (RET, NF-1, TMEM127, MAX). Cluster 1 genes associated PPGL are norepinephrine secreting whereas cluster 2 genes associated PPGL are epinephrine secreting. In children with PPGL, VHL mutations are the most common followed by SDHB and SDHD. Bilateral PCC are frequent in patients with VHL mutations whereas extra-adrenal PGL are frequent in SDHx mutations. SDHB related PPGL are frequently malignant. Genetic testing should be performed in all children with PPGL and prioritization of genetic testing based on clinical characteristics (extra-paraganglial manifestations, location and number of PPGL, biochemical phenotype and metastasis) may be cost-effective.

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SDHD Immunohistochemistry: A New Tool to ValidateSDHxMutations in Pheochromocytoma/Paraganglioma

Cited by 48 publications

References 20 publications

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)

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)

In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

Genotype–phenotype Correlation in Children with Pheochromocytoma and Paraganglioma

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