SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors

Oudijk, Lindsey; Gaal, José; Korpershoek, Esther; Nederveen, Francien H. van; Kelly, Lorna; Schiavon, Gaia; Verweij, Jaap; Mathijssen, Ron H.J.; Bakker, Michael A. den; Oldenburg, Rogier A.; Loon, Rosa L. E. van; O’Sullivan, Maureen; Krijger, Ronald R. de; Dinjens, Winand N.M.

doi:10.1038/modpathol.2012.186

Cited by 80 publications

(72 citation statements)

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“…The absence of immunostaining for SDHA, as well as SDHB, is helpful in identifying GISTs with possible SDH gene mutations. 58,58,[62][63][64][65][66] Approximately 50% of wild-type GISTs demonstrate high expression of IGF1R. 67 In SDH-deficient GISTs, upregulation of IGF1 and IGF2 may activate IGF1R in an autocrine manner (Figure 3b), resulting in signaling through both the MAP kinase and PI3 kinase/AKT pathways.…”

Section: Sdh-deficient Gistsmentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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Section: Sdh-deficient Gistsmentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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“…However, different mechanisms, including biallelic inactivating SDH mutations and epigenetic silencing, can coexist (e.g., SDH-deficient GISTs) 48,49,[56][57][58][59][60] (Supplementary Table S2 online). Notably, two sisters with an SDHA mutation (c.91C>T, p.Arg31*) were affected by SDHA/SDHB-immunonegative GISTs; one displayed LOH, whereas the other showed retention of heterozygosity, probably indicating a different mechanism of inactivation, such as promoter methylation of the WT allele.…”

Section: Mechanisms Of Biallelic Inactivationmentioning

confidence: 99%

“…Notably, two sisters with an SDHA mutation (c.91C>T, p.Arg31*) were affected by SDHA/SDHB-immunonegative GISTs; one displayed LOH, whereas the other showed retention of heterozygosity, probably indicating a different mechanism of inactivation, such as promoter methylation of the WT allele. 60 However, an undetected mutation seems to be the most likely mechanism. In addition, haploinsufficient and/or dominant negative effects for the SDH genes could be another mechanism of inactivation and have been indicated in particular cases: (i) bilateral adrenal medullary hyperplasia associated with a germ-line SDHB mutation (c.587G>A, p.Cys196Tyr) showing retention of heterozygosity 61 ; (ii and iii) SDHA/SDHB immunonegative GIST and PA in patients with SDHA mutations (c.91C>T, p.Arg31*; c.1873C>T, p.His625Tyr) displaying either retention of heterozygosity or paradoxical loss of the mutated SDHA allele, respectively 51,60 ; (iv) PCCs without loss of the WT SDHD allele arising in patients with SDHA mutations (c.341A>G, p.Tyr114Cys; c.441delG, p.Gly148Alafs*20) 62 ; and (v) somatic SDHD inactivation associated with consistent reduction of transcript levels in neural crest-derived, neuroendocrine, and gastrointestinal tumors.…”

Section: Mechanisms Of Biallelic Inactivationmentioning

confidence: 99%

“…60 However, an undetected mutation seems to be the most likely mechanism. In addition, haploinsufficient and/or dominant negative effects for the SDH genes could be another mechanism of inactivation and have been indicated in particular cases: (i) bilateral adrenal medullary hyperplasia associated with a germ-line SDHB mutation (c.587G>A, p.Cys196Tyr) showing retention of heterozygosity 61 ; (ii and iii) SDHA/SDHB immunonegative GIST and PA in patients with SDHA mutations (c.91C>T, p.Arg31*; c.1873C>T, p.His625Tyr) displaying either retention of heterozygosity or paradoxical loss of the mutated SDHA allele, respectively 51,60 ; (iv) PCCs without loss of the WT SDHD allele arising in patients with SDHA mutations (c.341A>G, p.Tyr114Cys; c.441delG, p.Gly148Alafs*20) 62 ; and (v) somatic SDHD inactivation associated with consistent reduction of transcript levels in neural crest-derived, neuroendocrine, and gastrointestinal tumors. 38,63 A recent report showed that somatic SDHC hypermethylation might be the cause of the Carney triad, a multitumoral syndrome of unknown etiology affecting five organs: paraganglia (PGL), adrenal gland (adrenocortical adenoma and PCC), lung (chondroma), stomach (GIST), and esophagus (leiomyoma).…”

Section: Mechanisms Of Biallelic Inactivationmentioning

confidence: 99%

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

Evenepoel

Papathomas

Krol

et al. 2015

Genetics in Medicine

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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...

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“…[13][14][15][16][17] Recent studies have identified SDHA as the most commonly mutated subunit, with SDHA mutations found in approximately 30% of SDHdeficient GISTs. [18][19][20][21] However, around 40% of SDH-deficient GISTs lack demonstrable mutations in an SDH subunit gene.…”

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confidence: 99%