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

Abstract

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...

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)

“…8,[71][72][73][74] In this rapidly expanding field, the importance of assessing the pathogenicity of a 'variant of unknown significance' has become a major and complex problem facing diagnostic laboratories. Our data further strengthen the role of SDHB/SDHA immunohistochemistry in determining the functionality of such variants, alone or in an integrated approach with in silico analysis 75,76 and/or western blot analysis, succinate dehydrogenase enzymatic assay, and mass spectrometric-based measurements of ratios of succinate/fumarate and other metabolites. [77][78][79] In the current study, we conclude that SDHB/ SDHA immunohistochemistry represents a reliable tool to identify patients with SDH-x mutations with an additional utility to evaluate the pathogenicity of SDH variants of unknown significance in the new next-generation sequencing era.…”

Structured assessment and followup for patients with hereditary kidney tumour syndromes

“…Clinical manifestations, in addition to paraganglioma and pheochromocytomas, include RCC and gastrointestinal stromal tumours (GIST), as summarized in Table 1. Of the six known PGL-PCC genes, mutations in three genes -SDHB, SDHC, and SDHD -are associated with a propensity for RCC 43 and we will limit our discussion to the management of patients with a mutation in these PGL-PCC genes. The median age of diagnosis for symptomatic RCC is 33 years, but has been shown to range from 15-62 years of age.…”

Succinat-Dehydrogenase(SDH)-defizientes Nierenzellkarzinom

“…Die Liste SDH-defizienter Neoplasien wächst stets, sodass aktuell neben den prototypischen Paragangliomsyndromen [3,26,33] auch manche gastrointestinale Stromatumoren (GIST [17,23]), Nierenzellkarzinom (NZK [10, 11, [27], seltene Hypophysenadenome [6,29] und andere noch seltenere Entitäten dazu zählen [6,29]. Im Folgenden werden die relevanten Aspekte des SDH-defizienten NZK dargestellt und im Hinblick auf ihre Differenzialdiagnose, Prognose und genetischen Hintergründe besprochen.…”

“…Das SDH-NZK kann zwar durch seine unspezifischen Symptome klinisch im Vordergrund stehen, wird aber (eher häufiger) im Rahmen einer Bildgebung bei diagnostiziertem Paragangliom, GIST oder einer anderen Erkrankungbzw. im RahmenvonScreening bei bekannter SDH-Keimbahnmutation festgestellt [6,26,29].…”