Gastrointestinal stromal tumors (GIST) harbor driver mutations of signal transduction kinases such as KIT, or, alternatively, manifest loss-of-function defects in the mitochondrial succinate ...dehydrogenase (SDH) complex, a component of the Krebs cycle and electron transport chain. We have uncovered a striking divergence between the DNA methylation profiles of SDH-deficient GIST (n = 24) versus KIT tyrosine kinase pathway-mutated GIST (n = 39). Infinium 450K methylation array analysis of formalin-fixed paraffin-embedded tissues disclosed an order of magnitude greater genomic hypermethylation relative to SDH-deficient GIST versus the KIT-mutant group (84.9 K vs. 8.4 K targets). Epigenomic divergence was further found among SDH-mutant paraganglioma/pheochromocytoma (n = 29), a developmentally distinct SDH-deficient tumor system. Comparison of SDH-mutant GIST with isocitrate dehydrogenase-mutant glioma, another Krebs cycle-defective tumor type, revealed comparable measures of global hypo- and hypermethylation. These data expose a vital connection between succinate metabolism and genomic DNA methylation during tumorigenesis, and generally implicate the mitochondrial Krebs cycle in nuclear epigenomic maintenance.
Warburg's metabolic hypothesis is based on the assumption that a cancer cell's respiration must be under attack, leading to its damage, in order to obtain increased glycolysis. Although this may not ...apply to all cancers, there is some evidence proving that primarily abnormally functioning mitochondrial complexes are indeed related to cancer development. Thus, mutations in complex II (succinate dehydrogenase (SDH)) lead to the formation of pheochromocytoma (PHEO)/paraganglioma (PGL). Mutations in one of the SDH genes (SDHx mutations) lead to succinate accumulation associated with very low fumarate levels, increased glutaminolysis, the generation of reactive oxygen species, and pseudohypoxia. This results in significant changes in signaling pathways (many of them dependent on the stabilization of hypoxia-inducible factor), including oxidative phosphorylation, glycolysis, specific expression profiles, as well as genomic instability and increased mutability resulting in tumor development. Although there is currently no very effective therapy for SDHx-related metastatic PHEOs/PGLs, targeting their fundamental metabolic abnormalities may provide a unique opportunity for the development of novel and more effective forms of therapy for these tumors.
Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor responsible for regulating genes related to angiogenesis and metabolism. This study aims to explore the effect of a previously ...unreported mutation c.C2473T (p.R825S) in the C-terminal transactivation domain (CTAD) of HIF-2α that we detected in tissue of patients with liver disease. We sequenced available liver and matched blood samples obtained during partial liver resection or liver transplantation performed for clinical indications including hepatocellular carcinoma and liver failure. In tandem, we constructed cell lines and a transgenic mouse model bearing the corresponding identified mutation in HIF-2α from which we extracted primary hepatocytes. Lipid accumulation was evaluated in these cells and liver tissue from the mouse model using Oil Red O staining and biochemical measurements. We identified a mutation in the CTAD of HIF-2α (c.C2473T; p.R825S) in 5 of 356 liver samples obtained from patients with hepatopathy and dyslipidemia. We found that introduction of this mutation into the mouse model led to an elevated triglyceride level, lipid droplet accumulation in liver of the mutant mice and in their extracted primary hepatocytes, and increased transcription of genes related to hepatic fatty acid transport and synthesis in the mutant compared to the control groups. In mutant mice and cells, the protein levels of nuclear HIF-2α and its target perilipin-2 (PLIN2), a lipid droplet-related gene, were also elevated. Decreased lipophagy was observed in mutant groups. Our study defines a subpopulation of dyslipidemia that is caused by this HIF-2α mutation. This may have implications for personalized treatment.
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Purpose Recently, a new renal cell cancer syndrome has been linked to germline mutation of multiple subunits ( SDHB / C / D ) of the Krebs cycle enzyme, succinate dehydrogenase. We report our ...experience with the diagnosis, evaluation and treatment of this novel form of hereditary kidney cancer. Materials and Methods Patients with suspected hereditary kidney cancer were enrolled on a National Cancer Institute institutional review board approved protocol to study inherited forms of kidney cancer. Individuals from families with germline SDHB , SDHC and SDHD mutations, and kidney cancer underwent comprehensive clinical and genetic evaluation. Results A total of 14 patients from 12 SDHB mutation families were evaluated. Patients presented with renal cell cancer at an early age (33 years, range 15 to 62), metastatic kidney cancer developed in 4 and some families had no manifestation other than kidney tumors. An additional family with 6 individuals found to have clear cell renal cell cancer that presented at a young average age (47 years, range 40 to 53) was identified with a germline SDHC mutation (R133X) Metastatic disease developed in 2 of these family members. A patient with a history of carotid body paragangliomas and an aggressive form of kidney cancer was evaluated from a family with a germline SDHD mutation. Conclusions SDH mutation associated renal cell carcinoma can be an aggressive type of kidney cancer, especially in younger individuals. Although detection and management of early tumors is most often associated with a good outcome, based on our initial experience with these patients and our long-term experience with hereditary leiomyomatosis and renal cell carcinoma, we recommend careful surveillance of patients at risk for SDH mutation associated renal cell carcinoma and wide surgical excision of renal tumors.
Carotid body paragangliomas (PGLs) are rare neuroendocrine tumors that develop within the adventitia of the medial aspect of the carotid bifurcation. Carotid body PGLs comprise about 65% of head and ...neck paragangliomas, however, their genetic background remains elusive. In the present study, we report one case of carotid body PGL with a somatic mutation in the gene encoding isocitrate dehydrogenase 2 (IDH2). The missense mutation in IDH2 resulted in R172G amino acid substitution, which exhibits neomorphic activity and production of D-2-hydroxyglutarate.
β-Arrestins are major regulators of G protein-coupled receptor-mediated signaling processes. Their potential roles in regulating adipocyte function in vivo remain unexplored. Here we report the novel ...finding that mice lacking β-arrestin-2 (barr2) selectively in adipocytes show significantly reduced adiposity and striking metabolic improvements when consuming excess calories. We demonstrate that these beneficial metabolic effects are due to enhanced signaling through adipocyte β3-adrenergic receptors (β3-ARs), indicating that barr2 represents a potent negative regulator of adipocyte β3-AR activity in vivo. Interestingly, essentially all beneficial metabolic effects caused by adipocyte barr2 deficiency are absent in adipocyte barr2-PRDM16 double KO mice, indicating that the metabolic improvements caused by the lack of barr2 in adipocytes are mediated by the browning/beiging of white adipose tissue. Our data support the novel concept that 'G protein-biased' β3-AR agonists that do not promote β3-AR/barr2 interactions may prove useful for the treatment of obesity and related metabolic disorders.
Purpose
Succinate dehydrogenase subunit B (
SDHB
) gene mutations are associated with an aggressive clinical disease course of pheochromocytoma/paraganglioma (PHEO/PGL). Limited information is ...available concerning PHEO/PGL penetrance among
SDHB
mutation carriers with regards to primary tumor location, specific mutation type, and gender. We assessed PHEO/PGL penetrance in
SDHB
mutation carriers and described the clinical presentation and disease course.
Methods
Asymptomatic relatives (
N
= 611) of 103 index patients were tested for
SDHB
mutations. Mutation carriers (
N
= 328) were offered PHEO/PGL screening, of which 241 participated and were included in penetrance analysis. For additional disease outcome analysis, the 103 index patients and 40 screened individuals who developed PHEO/PGL were included. Clinical data were collected between October 2004 and June 2016.
Results
Forty (16.60%) of the 241 screened individuals developed PHEO/PGL during the study. The penetrance estimate in this population was 49.80% (95% CI 29–74.9) at 85 years. A significantly higher age-related penetrance of disease was observed in males compared to females, with 50% penetrance achieved at age 74 vs. not reached. Age-related penetrance analysis demonstrated 4 mutations (Ile127Ser, IVS1+1G>T, Exon 1 deletion, Arg90X) presenting with a slower rate of disease development (50% penetrance ages, respectively: not achieved, 70, 63, 61 years) compared to Arg46X and Val140Phe mutations (50% penetrance at 38 years).
Conclusions
Here, we found a higher estimated penetrance compared to several other studies, and a striking difference in age-related penetrance between male and female
SDHB
mutation carriers with no association between mutation and gender or tumor location.
Adrenal neoplasms rarely occur in children. They can be diagnosed in the presence of endocrine, metabolic or neurological problems, an abdominal mass, more rarely an adrenal incidentaloma, or in the ...context of an adrenal mass discovered in the evaluation of childhood cancer including hematologic malignancy. According to standard medical practice, pediatric malignancies are almost always evaluated by
F-fluorodeoxyglucose positron emission tomography with computed tomography (
FFDG PET/CT). Nuclear imaging using specific radiotracers is also an important tool for diagnosing and staging neuroblastoma, pheochromocytoma, hormone hypersecretion, or indeterminate adrenal masses. The Hippocratic oath "primum non nocere" encourages limitation of radiation in children per the ALARA concept (as low as reasonably achievable) but should not lead to the under-use of nuclear imaging because of the potential risk of inaccurate diagnosis or underestimation of the extent of disease. As in adults, nuclear imaging in children should be performed in conjunction with hormone evaluation and morphological imaging.
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