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)

PurposeTo evaluate the role of germline SDHA mutation analysis by (1) comprehensive literature review, (2) description of novel germline SDHA mutations and (3) in silico structural prediction analysis of missense substitutions in SDHA.Patients and methodsA systematic literature review and a retrospective review of the molecular and clinical features of patients identified with putative germline variants in UK molecular genetic laboratories was performed. To evaluate the molecular consequences of SDHA missense variants, a novel model of the SDHA/B/C/D complex was generated and the structural effects of missense substitutions identified in the literature, our UK novel cohort and a further 32 “control missense variants” were predicted by the mCSM computational platform. These structural predictions were correlated with the results of tumor studies and other bioinformatic predictions.ResultsLiterature review revealed reports of 17 different germline SDHA variants in 47 affected individuals from 45 kindreds. A further 10 different variants in 15 previously unreported cases (seven novel variants in eight patients) were added from our UK series. In silico structural prediction studies of 11 candidate missense germline mutations suggested that most (63.7%) would destabilize the SDHA protomer, and that most (78.1%) rare SDHA missense variants present in a control data set (ESP6500) were also associated with impaired protein stability.ConclusionThe clinical spectrum of SDHA‐associated neoplasia differs from that of germline mutations in other SDH‐subunits. The interpretation of the significance of novel SDHA missense substitutions is challenging. We recommend that multiple investigations (e.g. tumor studies, metabolomic profiling) should be performed to aid classification of rare missense variants before genetic testing results are used to influence clinical management.

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“…), and a second patient with a HNPGL and a c.1534C>T (p.Arg512*) variant (Papathomas et al. ). No case of multifocal PCC/PGL was identified.…”

Section: Resultsmentioning

confidence: 99%

SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity

Casey

Ascher

Rattenberry

et al. 2017

Molec Gen & Gen Med

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“…In a study of a small number of cases in 2005, Dahia et al were first to show by immunohistochemistry and immunoblots that SDHB protein expression is lost in hereditary paraganglioma with SDHB or SDHD mutations (Dahia et al 2005). Subsequent large series showed that this occurs in hereditary tumors harboring loss-of-function germline mutations in any of the genes that separately encode components of the functional succinate dehydrogenase complex: SDHA, SDHB, SDHC, SDHD, and SDHAF2 (van , Burnichon et al 2010, Papathomas et al 2015. The loss of immunoreactivity in tumor cells typically occurs after loss or inactivation of the WT allele, while endothelial cells in the same tumor, which have not lost the WT allele, serve as positively stained controls.…”

Section: Thematic Reviewmentioning

confidence: 99%

“…Nonetheless, immunohistochemistry will likely continue to play a role in validating variants of uncertain significance (VUS) detected by NGS. The foundation for this use of immunohistochemistry is already partly established for SDHx-associated tumors (Papathomas et al 2015), although an updated SDHx database (Bayley et al 2005) containing all relevant mutations with accompanying data including immunohistochemistry is needed. Applicability to tumors associated with mutations of other genes such as MAX (Comino-Mendez et al 2011) may be limited by inadequate commercially available antibodies, the existence of immunoreactive but nonfunctional proteins, and other factors.…”

Section: Thematic Reviewmentioning

confidence: 99%

15 YEARS OF PARAGANGLIOMA: Pathology of pheochromocytoma and paraganglioma

Tischler¹,

deKrijger²

2015

Endocrine-Related Cancer

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Pathologists using their routine diagnostic tools can contribute both to the care of patients with pheochromocytoma/paraganglioma and to understanding the pathobiology of the tumors. They can document details of tissue organization and cytology that are accessible only by microscopy and can characterize admixtures of cell types that are morphologically distinct or show differential expression of immunohistochemical markers. Current roles and challenges for pathologists include differential diagnosis, identifying clues to the presence of hereditary disease, and effective communication of pathology information for clinical and research purposes. Future roles will increasingly involve risk stratification, identification of actionable targets for personalized therapies, and aiding the interpretation of molecular tests by helping characterize genetic variants of unknown significance. It remains to be determined to what extent the need for pathology input will be overshadowed by the availability of genetic testing and other molecular analyses at ever-decreasing cost, together with very effective clinical paradigms for risk stratification and patient care.

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“…SDHB expression is evaluated by looking for granular cytoplasmic staining in the paraganglioma cells. Loss of expression is an abnormal finding seen in the majority of PGLs with syndromically associated tumors from patients with SDHx germline mutations [21][22][23] and in Carney triad. Absent expression is only meaningful and can only be reported if there is staining of normal tissue (i.e.…”

Section: Immunohistochemical Evaluationmentioning

confidence: 99%

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas

Williams

Tischler

2017

Head and Neck Pathol

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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)

Cited by 181 publications

References 79 publications

SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity

SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity

15 YEARS OF PARAGANGLIOMA: Pathology of pheochromocytoma and paraganglioma

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas

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