Germline mutations in the mitochondrial 2-oxoglutarate/malate carrier (SLC25A11) gene confer predisposition to metastatic paragangliomas

Buffet, Alexandre; Morin, Aurélie; Castro-Vega, Luis-Jaime; Habarou, Florence; Lussey-Lepoutre, Charlotte; Letouze, Eric; Lefebvre, Herve; Guilhem, Isabelle; Haissaguerre, Magalie; Raingeard, I.; Padilla-Girola, Mathilde; Tran, Thi Ngoc Anh; Tchara, Lucien; Bertherat, Jérôme; Amar, Laurence; Ottolenghi, Chris; Burnichon, Nelly; Gimenez‐Roqueplo, Anne‐Paule; Favier, Judith

doi:10.1530/endoabs.56.oc7.4

Cited by 15 publications

(19 citation statements)

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“…Levels of 5hmC were assessed in FFPE tumor samples by immunohistochemical staining with a polyclonal rabbit antibody against 5hmC (Active Motif, AB_10013602) using standard methods as described above. Enzyme-linked immunosorbent assays (ELISA) were also used to analyze levels of 5-methyl cytosine (5mC) and 5hmC in SH-SY5Y wild-type (WT) cells and the DLST knockout SH-SY5Y clone S23, transfected with plasmids encoding either WT DLST, empty plasmid, the p.(Pro384Leu) variant or the p.(Pro389Leu) variant, using an assay previously described (18).…”

Section: Evaluation Of 5-hydroxymethyl Cytosine and 5-methyl Cytosine Levelsmentioning

confidence: 99%

Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma

Buffet

Zhang

Rebel

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors in which altered central metabolism appears to be a major driver of tumorigenesis, and many PPGL genes encode proteins involved in the tricarboxylic acid (TCA) cycle. Objective/design While around 40% of PPGL cases carry a variant in a known gene, many cases remain unexplained. In unexplained patients showing clear evidence of a familial burden or multiple tumors, we aimed to identify causative factors using genetic analysis of patient DNA and functional analyses of identified DNA variants in patient tumor material and engineered cell lines. Patients and Setting Patients with a likely familial cancer burden of pheochromocytomas and/or paragangliomas and under investigation in a clinical genetic and clinical research setting in university hospitals. Results While investigating unexplained PPGL cases, we identified a novel variant, c.1151C>T, p.(Pro384Leu), in exon 14 of the gene encoding dihydrolipoamide S-succinyltransferase (DLST), a component of the multi-enzyme complex 2-oxoglutarate dehydrogenase. Targeted sequence analysis of further unexplained cases identified a patient carrying a tumor with compound heterozygous variants in DLST, consisting of a germline variant, c.1121G>A, p.(Gly374Glu), together with a somatic missense variant identified in tumor DNA, c.1147A>G, p.(Thr383Ala), both located in exon 14. Using a range of in silico and functional assays we show that these variants are predicted to be pathogenic, profoundly impact enzyme activity and result in DNA hypermethylation. Conclusions The identification and functional analysis of these DLST variants further validates DLST as an additional PPGL gene involved in the TCA cycle.

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Section: Evaluation Of 5-hydroxymethyl Cytosine and 5-methyl Cytosine Levelsmentioning

confidence: 99%

Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma

Buffet

Zhang

Rebel

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…The SLC25A11 gene encodes for a mitochondrial carrier protein that is part of the malate‐asparate shuttle (this shuttle regenerates NADH to allow complex I to function), mediating the transport of α‐ketoglutarate from the mitochondrial matrix to the cytoplasm in exchange with malate. Preliminary results show that in SLC25A11 ‐mutated cells aspartate and glutamate concentration is increased inducing the pseudohypoxic pathway and hypermethylation …”

Section: Introductionmentioning

confidence: 97%

“…In terms of genomic features, tumors related to SDHx mutations are classified as cluster I, along with Von Hippel Lindau ( VHL ), fumarate hydratase ( FH ), malate dehydrogenase 2 ( MDH2 ), hypoxia induced factor ( HIF2α ) and isocitrate dehydrogenase ( IDH )‐mutations and the recently identified SLC25A11 . Cluster I germline mutations predispose to tumors characterized by a pseudohypoxic signature, in contrast to cluster II germline mutations, which are associated with abnormal kinase signaling pathways and include mutations in the genes of rearranged during transfection ( RET ), neurofibromatosis ( NF1 ), transmembrane protein 127 ( TMEM127 ), kinesin family member 1B ( KIF1B ), and MYC‐associated factor X ( MAX ).…”

Section: Introductionmentioning

confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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Succinate dehydrogenase (SDH) mutations lead to the accumulation of succinate, which acts as an oncometabolite. Germline SDHx mutations predispose to paraganglioma (PGL) and pheochromocytoma (PCC), as well as to renal cell carcinoma and gastro-intestinal stromal tumors. The SDHx genes were the first tumor suppressor genes discovered which encode for a mitochondrial enzyme, thereby supporting Otto Warburg's hypothesis in 1926 that a direct link existed between mitochondrial dysfunction and cancer. Accumulation of succinate is the hallmark of tumorigenesis in PGL and PCC. Succinate accumulation inhibits several α-ketoglutarate dioxygenases, thereby inducing the pseudohypoxia pathway and causing epigenetic changes. Moreover, SDH loss as a consequence of SDHx mutations can lead to reprogramming of cell metabolism. Metabolomics can be used as a diagnostic tool, as succinate and other metabolites can be measured in tumor tissue, plasma and urine with different techniques. Furthermore, these pathophysiological characteristics provide insight into therapeutic targets for metastatic disease. This review provides an overview of the pathophysiology and clinical implications of oncometabolite succinate in SDHx mutations. K E Y W O R D S oncometabolites, paraganglioma, pheochromocytoma, SDH mutation, succinate 1 | INTRODUCTION Mutations of genes encoding for the succinate dehydrogenase (SDH) complex, associated with familial paraganglioma (PGL) and pheochromocytoma (PCC), lead to accumulation of succinate, which disturbs the metabolic regulation of the cell. Nowadays metabolic dysregulation is recognized as one of the eight hallmarks of cancer. 1 Although germline mutations in SDHx genes are predominantly linked to PGL and PCC, these mutations also predispose to renal cell carcinoma (RCC), gastrointestinal stromal tumors (GISTs) and, possibly, pituitary adenomas. PCC, PGL and head and neck PGL (HNPGL) are rare neuroendocrine tumors arising from chromaffin cells that can synthesize and release catecholamines. Sympathetic PGLs are derived from sympathetic paraganglia in the chest, abdomen or pelvis. PCC are PGLs located in the adrenal medulla. 2 HNPGLs are derived from parasympathetic paraganglia. Common locations for HNPGLs include the carotid body and the middle ear, as well as the vagus nerve and internal jugular vein. While parasympathetic PGLs are most often non-functional tumors, PCC and sympathetic PGL release catecholamines into the circulation and can

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“…In this case report we present the second eldest patient to date, based on literature review, to be diagnosed with a pheochromocytoma at age 84 years old. The eldest patient to date was an 87-year-old male from Buffet et al's study on germline mutations in a metastatic paragangliomas [8]. Previously, Chenguan et al presented a case of a giant malignant pheochromocytoma in an 81-year-old male that measured 13.5x10.6x9.8 cm [9].…”

Section: Discussionmentioning

confidence: 99%

The Highs and Lows of an Unknown Pheochromocytoma in an Elderly Patient

DiMaria

Rasquin

Pinto

2019

Case Reports in Endocrinology

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Pheochromocytomas are rare catecholamine producing neuroendocrine tumors. The incidence of these tumors is estimated to affect 0.8 per 100,000 person-years and is most common in the fourth to fifth decade of life with equal prevalence in men and women. We describe a case of an 84-year-old male who presented with cycling episodes of severe hypertension and hypotension after an elective cardiac catheterization. Workup of the labile blood pressure revealed a large suprarenal mass and free serum metanephrines (MN) 104 nmol/L (reference range 0.0-0.49 nmol/L) and normetanephrines (NMN) of 24 nmol/L (reference range 0.0-0.89 nmol/L), confirming the diagnosis of a pheochromocytoma. The patient’s labile blood pressure was a challenge to manage medically and improved only after aggressive hydration and an alpha-adrenergic antagonist. Of note, this is the second eldest patient known to be published to date with a pheochromocytoma.

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Germline mutations in the mitochondrial 2-oxoglutarate/malate carrier (SLC25A11) gene confer predisposition to metastatic paragangliomas

Cited by 15 publications

References 0 publications

Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma

Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

The Highs and Lows of an Unknown Pheochromocytoma in an Elderly Patient

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