A novel germline SDHB mutation in a gastrointestinal stromal tumor patient without bona fide features of the Carney–Stratakis dyad

Celestino, Ricardo; Lima, Jorge; Faustino, Alexandra; Máximo, Valdemar; Gouveia, António; Vinagre, João; Soares, Paula; Lopes, José Manuel

doi:10.1007/s10689-011-9499-x

Cited by 17 publications

(22 citation statements)

References 37 publications

(45 reference statements)

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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%

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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Section: Mechanisms Of Biallelic Inactivationmentioning

confidence: 99%

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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“…21 Negative and positive controls were used simultaneously to ensure specificity and reliability of the staining process. Previously tested positive cases of oncocytic variant of papillary thyroid carcinoma were used as positive controls.…”

Section: Methodsmentioning

confidence: 99%

“…Tumor DNA was extracted from all 25 WT GISTs as previously described, 21 and all the cases were evaluated by PCR and DNA sequencing for the presence of SDHB, SDHC and SDHD point mutations and deletions of exon 1 in SDHB, as previously described. 35,36 Briefly the PCR mixture, 25 ml in total, contained 100 ng of genomic DNA, 1 ml dNTP's (5mM each; Bioron GmbH, Ludwigshafen, Germany), 1 ml of each primer (10mM), 36 5 ml 5Â Green GoTaq Flexi Buffer, 2.5 ml MgCl 2 (25 mM) and 0.15 U GoTaq Flexi DNA Polymerase (Promega, Madison, WI, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Case 1 was previously reported by our group. 21 None of the germline-mutated cases expressed SDHB in the tumors.…”

Section: Sdh Molecular Alterations In Wt Gistsmentioning

confidence: 95%

“…20 Recently, loss of function of succinate dehydrogenase (SDH) complex was proposed as another alternative molecular mechanism in KIT/PDGFRA/BRAF WT GISTs. [21][22][23][24][25][26][27] In Carney-Stratakis dyad, patients develop multifocal GISTs and paraganglioma (PGL), 28,29 and GISTs are known to display deficient SDH protein expression. 22 Further molecular studies addressing Carney-Stratakis syndrome patients disclosed the presence of germline mutations of the SDH subunits B (SDHB), C (SDHC) and D (SDHD).…”

Section: Introductionmentioning

confidence: 99%

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Molecular alterations and expression of succinate dehydrogenase complex in wild-type KIT/PDGFRA/BRAF gastrointestinal stromal tumors

et al. 2012

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, disclosing somatic KIT, PDGFRA and BRAF mutations. Loss of function of succinate dehydrogenase (SDH) complex is an alternative molecular mechanism in GISTs, namely in carriers of germline mutations of the SDH complex that develop Carney-Stratakis dyad characterized by multifocal GISTs and multicentric paragangliomas (PGLs). We studied a series of 25 apparently sporadic primary wild-type (WT) KIT/PDGFRA/BRAF GISTs occurring in patients without personal or familial history of PGLs, re-evaluated clinicopathological features and analyzed molecular alterations and immunohistochemistry expression of SDH complex. As control, we used a series of well characterized 49 KIT/PDGFRA/BRAF-mutated GISTs. SDHB expression was absent in 20% and SDHB germline mutations were detected in 12% of WT GISTs. Germline SDHB mutations were significantly associated to younger age at diagnosis. A significant reduction in SDHB expression in WT GISTs was found when compared with KIT/ PDGFRA/BRAF-mutated GISTs. No significant differences were found when comparing DOG-1 and c-KIT expression in WT, SDHB-mutated and KIT/PDGFRA/BRAF-mutated GISTs. Our results confirm the occurrence of germline SDH genes mutations in isolated, apparently sporadic WT GISTs. WT KIT/PDGFRA/BRAF GISTs without SDHB or SDHA/SDHB expression may correspond to Carney-Stratakis dyad or Carney triad. Most importantly, the possibility of PGLs (Carney-Stratakis dyad) and/or pulmonary chondroma (Carney triad) should be addressed in these patients and their kindred.

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GISTogram: a graphic presentation of the growing GIST complexity

2013

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They have represented a paradigm of molecular-targeted therapies for solid tumors since the discovery of KIT mutations and KIT expression in GIST in 1998, which opened the way to the use of imatinib, a tyrosine kinase inhibitor able to inhibit the growth of cells expressing KIT-mutant isoforms. Since then, accumulating evidence revealed the rather heterogeneous nature of GIST, implying possible different diagnostic and therapeutic approaches for each specific case, leading to the development of drugs alternative to imatinib. In this brief commentary, we graphically represent the historical growing of genotype and phenotype evidence on GIST since 1998 in its increasing complexity by building up a graph, which we have called "GISTogram", that visually conveys most of GIST-characterizing features and the probability for each of them, either alone or in combination, to be observed in a single GIST case.

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A novel germline SDHB mutation in a gastrointestinal stromal tumor patient without bona fide features of the Carney–Stratakis dyad

Cited by 17 publications

References 37 publications

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

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

Molecular alterations and expression of succinate dehydrogenase complex in wild-type KIT/PDGFRA/BRAF gastrointestinal stromal tumors

GISTogram: a graphic presentation of the growing GIST complexity

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