Succinate Dehydrogenase Mutation Underlies Global Epigenomic Divergence in Gastrointestinal Stromal Tumor

Killian, Jonathan Keith; Kim, Su Young; Miettinen, Markku; Smith, Carly; Merino, María J.; Tsokos, Maria; Quezado, Martha; Smith, William I.; Jahromi, Mona S.; Xekouki, Paraskevi; Szarek, Eva; Walker, Robert L.; Lasota, Jerzy; Raffeld, Mark; Klotzle, Brandy; Wang, Zengfeng; Jones, Laura; Zhu, Yuelin J.; Wang, Yonghong; Waterfall, Joshua J.; O’Sullivan, Maureen; Bibikova, Marina; Pacák, Karel; Stratakis, Constantine A.; Janeway, Katherine A.; Schiffman, Joshua D.; Fan, Jie; Helman, Lee J.; Meltzer, Paul S.

doi:10.1158/2159-8290.cd-13-0092

Cited by 298 publications

(281 citation statements)

References 28 publications

Supporting

Mentioning

258

Contrasting

Unclassified

Order By: Relevance

“…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). 10,61 The GISTs in affected patients show either loss or somatic mutation (second hit) of the remaining wild-type allele.…”

Section: Sdh-deficient Gistsmentioning

confidence: 99%

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

Section: Sdh-deficient Gistsmentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

View full text Add to dashboard Cite

show abstract

“…Importantly, both SDH mutant PCCs/PGLs as well as GISTs have been recently shown to display a hypermethylator phenotype, exposing a vital interplay among succinate metabolism, epigenetic disruptions, and tissue-specific tumorigenesis. 37,65,80 conclusion Familial PCC/PGL syndromes were initially thought to predispose only to PCCs and PGLs, but several tumors, including GISTs, RCCs, and PAs, have expanded the SDH-associated tumor spectrum. Extensive clinical variability can be expected, even among carriers of an identical SDH germ-line mutation, with tumor phenotypes being only partially expressed, as in the Carney-Stratakis dyad.…”

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

View full text Add to dashboard Cite

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...

show abstract

“…28,29 In comparison to the well-established use of HM-450K assays on FF tissues and cell lines, the application of FFPE-derived DNA in HM-450K assays may be hindered due to a lack of sufficient evidence proving the feasibility and reproducibility of this approach. Few recent studies describing the performance of HM-450K assays on FFPE tissue have shown a good concordance between matched FF and FFPE tissue when applying the Illumina DNA restoration procedure on DNA from fixed tissue.…”

Section: Ffpe Tissue Epigenomics Tc De Ruijter Et Almentioning

confidence: 99%

Formalin-fixed, paraffin-embedded (FFPE) tissue epigenomics using Infinium HumanMethylation450 BeadChip assays

Ruijter

Hoon

Slaats

et al. 2015

Laboratory Investigation

View full text Add to dashboard Cite

Current genome-wide methods to detect DNA-methylation in healthy and diseased tissue require high-quality DNA from fresh-frozen (FF) samples. However, well-annotated clinical samples are mostly available as formalin-fixed, paraffinembedded (FFPE) tissues containing poor-quality DNA. To overcome this limitation, we here aimed to evaluate a DNA restoration protocol for usage with the genome-wide Infinium HumanMethylation450 BeadChip assay (HM-450K). Sixty-six DNA samples from normal colon (n = 9) and breast cancer (n = 11) were interrogated separately using HM-450K. Analyses included matched FF/FFPE samples and technical duplicates. FFPE DNA was processed with (FFPEr) or without a DNA restoration protocol (Illumina). Differentially methylated genes were finally validated in 24 additional FFPE tissues using nested methylation-specific PCR (MSP). In summary, β-values correlation between FFPEr duplicates was high (ρ = 0.9927 (s.d. ± 0.0015)). Matched FF/FFPEr correlation was also high (ρ = 0.9590 (s.d. ± 0.0184)) compared with matched FF/FFPE (ρ = 0.8051 (s.d. ± 0.1028). Probe detection rate in FFPEr samples (98.37%, s.d. ± 0.66) was comparable to FF samples (99.98%, s.d. ± 0.019) and substantially lower in FFPE samples (82.31%, s.d. ± 18.65). Assay robustness was not decreased by sample archival age up to 10 years. We could also demonstrate no decrease in assay robustness when using 100 ng of DNA input only. Four out of the five selected differentially methylated genes could be validated by MSP. The gene failing validation by PCR showed high variation of CpG β-values in primer-binding sites. In conclusion, by using the FFPE DNA restoration protocol, HM-450K assays provide robust, accurate and reproducible results with FFPE tissue-derived DNA, which are comparable to those obtained with FF tissue. Most importantly, differentially methylated genes can be validated using more sensitive techniques, such as nested MSP, altogether providing an epigenomics platform for molecular pathological epidemiology research on archived samples with limited tissue amount. Epigenomic changes are recognised as important factors in tumour initiation, growth and progression. Global and local DNA-methylation patterns are frequently altered in cancer cells, resulting in genomic instability and diminished or elevated expression of tumour-suppressor genes or oncogenes, respectively, driving malignant transformation, growth promotion and metastasis (reviewed in Jones and Baylin 1 and Petronis 2 ). In the clinical setting, cancer-specific DNA-methylation changes are increasingly evaluated as biomarkers for early detection, staging or patient prognosis.In addition, a role for DNA-methylation changes in mediating either cancer drug resistance or drug sensitivity has been hypothesised and verified. [3][4][5][6] Therefore, the in-depth study of the cancer DNA-methylome holds promise to provide important clues as to which genes and biological networks are affected at tumour initiation and progression. Furthermore, it will provide clues as to which g...

show abstract

Succinate Dehydrogenase Mutation Underlies Global Epigenomic Divergence in Gastrointestinal Stromal Tumor

Cited by 298 publications

References 28 publications

Gastrointestinal stromal tumors: what do we know now?

Gastrointestinal stromal tumors: what do we know now?

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

Formalin-fixed, paraffin-embedded (FFPE) tissue epigenomics using Infinium HumanMethylation450 BeadChip assays

Contact Info

Product

Resources

About