SDH deficient renal tumours WGS
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ABSTRACT:
PROVIDER: EGAS00001004102 | EGA |
REPOSITORIES: EGA
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Project description:Succinate dehydrogenase (SDH) deficient renal cancers are a rare and understudied subtype of renal cancer. As such they represent an unmet need in kidney cancer research. Here, we seek to describe the genomics and transcriptomics of SDH deficient renal cancers by sequencing five such tumours.
| EGAS00001004103 | EGA
Project description:Succinate dehydrogenase (SDH) is a mitochondrial protein complex responsible for the oxidation of succinate to fumarate in the tricarboxylic acid cycle. Loss-of-function mutations in any of the SDH genes are associated with susceptibility to develop neu-roendrocrine neoplasms and renal cell carcinoma. However, the impact of SDH loss on cell metabolism and the mechanisms enabling growth of SDH-defective cells are largely unexplored. To address this issue we generated Sdhb-ablated kidney mouse cells and compared their transcriptomic profile with that of Sdhb-proficient cells. Results of this gene analysis are provided in the here deposited gene array.
2016-01-22 | E-MTAB-4349 | biostudies-arrayexpress
Project description:<p>Metabolic lesions with pleiotropic effects on epigenetic regulation and other cellular processes are widely implicated in cancer, yet their oncogenic mechanisms remain poorly understood. Succinate dehydrogenase (SDH) deficiency causes a subset of gastrointestinal stromal tumors (GISTs) with DNA hyper-methylation. Here we associate this hyper-methylation with changes in chromosome topology that activate oncogenic programs. To investigate epigenetic alterations in this disease, we systematically mapped DNA methylation, CTCF insulators, enhancers and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs. Although these respective subtypes share similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on disrupted insulators that partitions super-enhancers from FGF3, FGF4 and the KIT oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancers and oncogenes. CRISPR-mediated excision of the corresponding CTCF motif in an SDH-intact model disrupted the boundary and up-regulated FGFs and KIT expression. Our findings reveal how a metabolic lesion destabilizes chromatin structure to facilitate the initiation and selection of epigenetic alterations that drive oncogenic programs in the absence of canonical mutations.</p>
| phs001906 | dbGaP
Project description:Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we evaluated novel treatment approaches in newly generated models of FH- and SDHB-deficient RCC.
2022-05-28 | GSE204846 | GEO
Project description:Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood. A subset of gastrointestinal stromal tumors (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH)-deficiency and global DNA hyper-methylation. Here we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant, and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary and strongly up-regulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetic state of the parental tumor, including hyper-methylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibitor, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers.
2019-10-16 | GSE107447 | GEO
Project description:Pediatric GIST commonly harbors a disabled succinate dehydrogenase complex (SDH), which yields tumors with highly conserved genomes but characteristic epigenomic signatures. Mysteriously, nearly half of such SDH-deficient GIST, including tumors from Carney Triad patients, lack identifiable mutations in SDH component genes and genes required for complex assembly (SDHA, SDHB, SDHC, SDHD, SDHAF, termed SDHx). Genomic sequencing coupled with DNA methylation and transcriptional profiling have exposed SDHC promoter-specific CpG island epimutation and concomitant gene silencing in the majority of SDHx-WT GIST.
2015-01-02 | GSE56670 | GEO
Project description:Activation of macrophages by inflammatory stimuli leads to reprogramming of mitochondrial metabolism to support the production of pro-inflammatory cytokines. Hallmarks of this metabolic rewiring are downregulation of α-ketoglutarate formation via isocitrate dehydrogenase (IDH) and accumulation of glutamine-derived succinate, which enhances the inflammatory response via the activity of succinate dehydrogenase (SDH). Here, we identify the nuclear receptor Nur77 (Nr4a1) as a key regulator of the pro-inflammatory metabolic switch in macrophages. Nur77-deficient macrophages fail to downregulate IDH expression and accumulate higher levels of succinate and other downstream TCA cycle metabolites in response to an inflammatory stimulus. Consequently, these macrophages produce more nitric oxide and pro-inflammatory cytokines in an SDH-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis development and leads to increased systemic succinate levels. In conclusion, Nur77 supports an anti-inflammatory metabolic state in macrophages that protects against chronic inflammatory diseases such as atherosclerosis.
2018-08-21 | GSE102393 | GEO
Project description:Activation of macrophages by inflammatory stimuli leads to reprogramming of mitochondrial metabolism to support the production of pro-inflammatory cytokines. Hallmarks of this metabolic rewiring are downregulation of α-ketoglutarate formation via isocitrate dehydrogenase (IDH) and accumulation of glutamine-derived succinate, which enhances the inflammatory response via the activity of succinate dehydrogenase (SDH). Here, we identify the nuclear receptor Nur77 (Nr4a1) as a key regulator of the pro-inflammatory metabolic switch in macrophages. Nur77-deficient macrophages fail to downregulate IDH expression and accumulate higher levels of succinate and other downstream TCA cycle metabolites in response to an inflammatory stimulus. Consequently, these macrophages produce more nitric oxide and pro-inflammatory cytokines in an SDH-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis development and leads to increased systemic succinate levels. In conclusion, Nur77 supports an anti-inflammatory metabolic state in macrophages that protects against chronic inflammatory diseases such as atherosclerosis.
2018-08-21 | GSE102359 | GEO
Project description:Pediatric GIST commonly harbors a disabled succinate dehydrogenase complex (SDH), which yields tumors with highly conserved genomes but characteristic epigenomic signatures. Mysteriously, nearly half of such SDH-deficient GIST, including tumors from Carney Triad patients, lack identifiable mutations in SDH component genes and genes required for complex assembly (SDHA, SDHB, SDHC, SDHD, SDHAF, termed SDHx). Genomic sequencing coupled with DNA methylation and transcriptional profiling have exposed SDHC promoter-specific CpG island epimutation and concomitant gene silencing in the majority of SDHx-WT GIST. We performed whole genome expression profiling on 20 FFPE dSDH GIST tumors using Affymetrix U133P2 arrays which contain >54K gene target probesets. Included here were data from 7 SDHx-w.t. and 13 SDHx mutants that passed array QC.
2015-01-02 | E-GEOD-56670 | biostudies-arrayexpress
Project description:Background & Aims: Succinate dehydrogenase enzyme (SDH) is frequently found to be diminished in Hepatocellular carcinoma (HCC) patient samples, and SDH reduction is associated with elevated succinate level and poor prognosis in HCC patients. But the underlying mechanisms about how impaired SDH activity promotes HCC malignancy remain unclear. Approach & Results: In this study, we observed remarkable downregulations of SDH subunits A and B (SDHA/B) in chronic liver injury-induced murine HCC models and HCC patient samples. Subsequent RNA sequencing, hematoxylin & eosin (H&E) staining and immunohistochemistry (IHC) analyses of HCC samples revealed that Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) were significantly upregulated in HCC, with their levels inversely correlating with that of SDHA/B. The protein stability of YAP/TAZ was greatly enhanced in SDHA/B-depleted HCC cells along with accumulation of succinate. Further mechanistic analyses demonstrated that impaired activity of SDHA/B resulted in succinate accumulation which facilitated the removal of NEDDylation on cullin1, therefore disrupted the E3 ubiquitin ligase SCFβ-TrCP complex, consequently led to YAP/TAZ stabilization and activation in HCC cells. The accelerated in vitro cell proliferation and in vivo tumor growth caused by SDHA/B reduction or succinate exposure were largely dependent on the aberrant activation of YAP/TAZ. Conclusions: Our study demonstrated that SDHA/B reduction promotes HCC proliferation by preventing the proteasomal degradation of YAP/TAZ through modulating cullin1 NEDDylation, thus addicts SDH-deficient HCC cells to YAP/TAZ pathway and renders these cells vulnerable to YAP/TAZ inhibition. Our findings warrant further investigation on the therapeutic effects of targeting YAP/TAZ in HCC patients displaying reduced SDHA/B or elevated succinate levels.
2023-05-31 | GSE207147 | GEO