Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

Mason, Emily F.; Hornick, Jason L.

doi:10.1038/modpathol.2013.86

Cited by 63 publications

(47 citation statements)

References 43 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, these structural similarities suggest that succinate, fumarate and D-2-HG may act as competitive inhibitors of -KG to interfere with the function of -KG-dependent dioxygenases. This hypothesis was supported by a series of experiments both in vitro and in vivo [27,63,[71][72][73][74]84]. Moreover, structural analyses have shown that succinate and fumarate could bind the -KGdependent dioxygenases in their catalytic core just like -KG, such as FIH and AlkB [70,86].…”

Section: Succinate Fumarate and D-2-hg Are Structurally Similar To Amentioning

confidence: 48%

“…Furthermore, two DNA methylation profiling studies found that SDH mutations in gastrointestinal stromal tumors, paragangliomas and pheochromocytomas were associated with genomic hypermethylation [72,73]. In addition, decreased levels of 5-hydroxymethylcytosine were associated with SDH mutations in gastrointestinal stromal tumors [74]. Taken together, the in vivo evidence strongly supports that mutation in FH or SDH results in global genome changes in DNA methylation, likely due to inhibition of TET proteins by fumarate or succinate, thus leading to epigenetic alterations in cancers.…”

Section: Sdh and Fh Mutants Inhibit Multiple -Kg Dependent Dioxygenasesmentioning

confidence: 99%

See 1 more Smart Citation

Metabolic alteration in tumorigenesis

Yang

Guan

2013

Sci. China Life Sci.

View full text Add to dashboard Cite

Altered metabolism in cancer was first discovered by Otto Warburg early last century. Although the Warburg Effect has been widely used in tumor detection, relatively little progress had been made in mechanistic understanding of cancer metabolism in the subsequent eight decades. Genetic studies have recently identified mutations in human cancer targeting multiple enzymes involved in intermediate metabolism. One emerging mechanism common to these mutant enzymes is the accumulation of a metabolite that alters the epigenetic control. Otto Warburg [1,2] first discovered that cancer cells displayed enhanced glucose uptake and aerobic glycolysis, a phenomenon often referred as the Warburg Effect nowadays. Although the mechanism underlying the Warburg Effect is still not fully understood, increased uptake of glucose provides the basis to exploit its clinical application by 18 F-deoxyglucose positron emission tomography (PET) for tumor detection [3,4]. Decades after the Warburg Effect was discovered, the mechanistic insights of how metabolic alterations contribute to tumorigenesis are just emerging. Recent studies have revealed that eight metabolic genes, FH, SDHA, SDHB, SDHC, SDHD, SDHAF2, IDH1 and IDH2, encoding for subunits of four different metabolic enzymes, fumarate hydratase (FH), succinate dehydrogenase (SDH), and isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), were mutated in a number of human cancers [5]. These findings provide compelling genetic evidence supporting the notion that altered metabolism contributes to, as opposed to the consequence of, tumorigenesis. Here, we first briefly discuss how metabolism is reprogrammed to support cancer cell proliferation. We then focus on one emerging mechanism that is common to the mutations targeting all four metabolic enzymes in accumulating a metabolite to alter the epigenetic modifications in human cancer.

show abstract

Section: Succinate Fumarate and D-2-hg Are Structurally Similar To Amentioning

confidence: 48%

Section: Sdh and Fh Mutants Inhibit Multiple -Kg Dependent Dioxygenasesmentioning

confidence: 99%

Metabolic alteration in tumorigenesis

Yang

Guan

2013

Sci. China Life Sci.

View full text Add to dashboard Cite

show abstract

“…This results in increased transcription of HIF1a-regulated genes and decreased DNA demethylation (Figure 3b). 59 Indeed, SDH-deficient GISTs show a global increase in DNA methylation similar to that seen in gliomas and leukemias with IDH1 and IDH2 mutations. 60 Germline mutations in SDHA, SDHB, or SDHC increase the risk not only for the development of one or more SDH-deficient GISTs but also for paragangliomas (Carney-Stratakis syndrome).…”

Section: Sdh-deficient Gistsmentioning

confidence: 95%

Gastrointestinal stromal tumors: what do we know now?

2014

View full text Add to dashboard Cite

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.

show abstract

“…39 Recently few studies have reported aberrant methylation status in GIST patients, particularly those with KIT/ PDGFRA wild type. 40,41 As the methylation status of various genes greatly influences the diagnosis and prognosis of several tumours, it is reasonable to think that genetic polymorphisms in key enzymes of the folate metabolism may perturb this pathway and have the potential of becoming biomarkers of prognosis. To explore this hypothesis, we investigated the association of the selected genetic polymorphisms with OS.…”

Section: Discussionmentioning

confidence: 99%

Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome

et al. 2014

View full text Add to dashboard Cite

The folate metabolism pathway has a crucial role in tumorigenesis as it supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. Despite its importance, little is known about the influence of the folate pathway on gastrointestinal stromal tumour (GIST), a rare tumour with an incidence ranging between 6 and 19.6 cases per million worldwide. The importance of folate metabolism led us to investigate the influence of polymorphisms in the genes coding folate-metabolising enzymes on GIST susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 13 polymorphisms in 8 genes in 60 cases and 153 controls. The TS 6-bp deletion allele (formerly rs34489327, delTInsTTAAAG) was associated with reduced risk of GIST (OR = 0.20, 95% CI 0.05-0.67, P = 0.0032). Selected polymorphisms in patients stratified by age, gender, and other main molecular and clinical characteristics showed that few genotypes may show a likely correlation. We also observed a significant association between the RFC AA/AG genotype and time to progression (HR = 0.107, 95% CI 0.014-0.82; P = 0.032). Furthermore, we observed a tendency towards an association between the SHMT1 variant allele (TT, rs1979277) and early death (HR = 4.53, 95% CI 0.77-26.58, P = 0.087). Aware of the strengths and limitations of the study, these results suggest that polymorphisms may modify the risk of GIST and clinical outcome, pointing to the necessity for further investigations with information on folate plasma levels and a larger study population. INTRODUCTIONFolate metabolism supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. DNA methylation status is essential for normal development and maintenance of cellular homeostasis and functions in adult organisms, including silencing of repetitive DNA elements, proper expression of genetic information and maintenance of genomic structural integrity. 1 The accurate maintenance of DNA synthesis, repair, and methylation patterns is fundamental, and its balance in mature cells is maintained by the concerted action of more than 30 enzymes. 2 These enzymes are highly polymorphic, and several functional genetic polymorphisms have been attracting research interest, as they may be responsible for altered DNA synthesis, repair and methylation processes, all of which are crucial in relation to carcinogenesis. Aberrant methylation patterns have been associated with various diseases including cancer and neurodegenerative diseases. 3,4 In addition, polymorphisms in genes involved in the folate metabolisms have been associated with cancer risk, including colorectal and gastric cancer, vascular disease, depression, and Down's syndrome. 5 Currently, there are evidences of an association between DNA methylation level and polymorphisms in folate metabolism genes. 6,7

show abstract

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

Cited by 63 publications

References 43 publications

Metabolic alteration in tumorigenesis

Metabolic alteration in tumorigenesis

Gastrointestinal stromal tumors: what do we know now?

Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome

Contact Info

Product

Resources

About