Reduced expression and loss of heterozygosity of the SDHD gene in colorectal and gastric cancer

Habano, Wataru; Sugai, Tamotsu; Nakamura, Shinichi; Uesugi, Noriyuki; Higuchi, Taro; Terashima, Masanori; Horiuchi, Saburo

doi:10.3892/or.10.5.1375

Cited by 41 publications

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“…Since the average age of the mice in our colony does not reach 1 year, we cannot exclude the possibility that tumors will appear in aged mice. As in the CB, somatic SDHD deficiency could also produce constitutive subclinical alterations in other organs, especially in those containing paraneural tissues, where the decrease of complex II activity precedes the appearance of diseases (8,13,17). The SDHD knockout mouse model could help to provide prognostic insights for individuals carrying mutations.…”

Section: Discussionmentioning

confidence: 99%

The Mitochondrial SDHD Gene Is Required for Early Embryogenesis, and Its Partial Deficiency Results in Persistent Carotid Body Glomus Cell Activation with Full Responsiveness to Hypoxia

Piruat

Pintado

Ortega-Sáenz

et al. 2004

Molecular and Cellular Biology

138

111

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The SDHD gene encodes one of the two membrane-anchoring proteins of the succinate dehydrogenase (complex II) of the mitochondrial electron transport chain. This gene has recently been proposed to be involved in oxygen sensing because mutations that cause loss of its function produce hereditary familiar paraganglioma, a tumor of the carotid body (CB), the main arterial chemoreceptor that senses oxygen levels in the blood. Here, we report the generation of a SDHD knockout mouse, which to our knowledge is the first mammalian model lacking a protein of the electron transport chain. Homozygous SDHD ؊/؊ animals die at early embryonic stages. Heterozygous SDHD ؉/؊ mice show a general, noncompensated deficiency of succinate dehydrogenase activity without alterations in body weight or major physiological dysfunction. The responsiveness to hypoxia of CBs from SDHD ؉/؊ mice remains intact, although the loss of an SDHD allele results in abnormal enhancement of resting CB activity due to a decrease of K ؉ conductance and persistent Ca 2؉ influx into glomus cells. This CB overactivity is linked to a subtle glomus cell hypertrophy and hyperplasia. These observations indicate that constitutive activation of SDHD ؉/؊ glomus cells precedes CB tumor transformation. They also suggest that, contrary to previous beliefs, mitochondrial complex II is not directly involved in CB oxygen sensing. Mitochondrial complex II (succinate dehydrogenase [SDH])plays major biological roles in the Krebs cycle and the mitochondrial electron transport chain, oxidizing succinate to fumarate and transferring electrons to the ubiquinone pool (9, 12). SDH has also been proposed to have an antioxidant function, protecting against superoxide production in mitochondria, and to participate in oxygen (O 2 ) sensing (3,7,22,27). Deficiencies of any of the four subunits of SDH (A, B, C, and D) are associated with a broad spectrum of human diseases, ranging from myo-and encephalopathies to aging and tumor formation. Mutations in SDHA, the matrix-faced flavoprotein, result in dysfunction of the energy metabolism, e.g., Leigh syndrome or exercise intolerance, whereas mutations either in the iron-sulfur protein SDHB or in SDHC and SDHD, the membrane-anchoring proteins that contain one heme and are essential for ubiquinone binding, are more often associated with pheochromocytoma and paraganglioma (1,22,23). Specifically, mutations in SDHD are the main cause of familiar hereditary paraganglioma (PGL) (3) a mostly benign, highly vascularized tumor of the carotid body (CB). SDHD is the first tumor suppressor gene identified which encodes a mitochondrial protein.The CB is the main arterial chemoreceptor that senses blood O 2 concentration. It is a highly irrigated bilateral organ, located at the bifurcation of the carotid artery and derived from the neural crest. Upon exposure to acute hypoxia, neurosecretory CB glomus cells release transmitters which activate afferent sensory fibers connected with brain stem centers to elicit hyperventilation and sympathetic activation ...

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Section: Discussionmentioning

confidence: 99%

The Mitochondrial SDHD Gene Is Required for Early Embryogenesis, and Its Partial Deficiency Results in Persistent Carotid Body Glomus Cell Activation with Full Responsiveness to Hypoxia

Piruat

Pintado

Ortega-Sáenz

et al. 2004

Molecular and Cellular Biology

138

111

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“…However, SDHx gene haploinsufficiency contributing to the tumor formation cannot be ruled out from our analyses. Haploinsufficient effects for the SDHx genes have been suggested in: i) bilateral adrenal medullary hyperplasia associated with a germline SDHB mutation showing retention of heterozygosity (38); ii) PCCs without loss of the WT SDHD allele arising in SDHD-mutated patients (39); and iii) somatic SDHD inactivation being accompanied by consistent reduction of transcript levels in various tumors (40,41). Albeit, in mouse models, no indications were obtained for an SDHB/SDHD haploinsufficient contribution to tumorigenesis (42,43) Table 1), with a further 31 PAs co-occurring with PCCs and/or PGLs pointing to a causative association with SDHx, MEN1, or other yet unidentified predisposing genes (44,45,46).…”

Section: Discussionmentioning

confidence: 99%

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis

Papathomas

Gaal

Corssmit

et al. 2014

European Journal of Endocrinology

118

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Objective: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated. Design and methods: Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC. Printed in Great BritainPublished by Bioscientifica Ltd.Conclusions: These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.

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“…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). 64,65 This suggests that epigenetic silencing of SDH could also be an important mechanism involved in tumor development and could explain SDH deficiency in the absence of germ-line mutations.…”

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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Reduced expression and loss of heterozygosity of the SDHD gene in colorectal and gastric cancer

Cited by 41 publications

References 0 publications

The Mitochondrial SDHD Gene Is Required for Early Embryogenesis, and Its Partial Deficiency Results in Persistent Carotid Body Glomus Cell Activation with Full Responsiveness to Hypoxia

The Mitochondrial SDHD Gene Is Required for Early Embryogenesis, and Its Partial Deficiency Results in Persistent Carotid Body Glomus Cell Activation with Full Responsiveness to Hypoxia

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis

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

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