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Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients.

ABSTRACT: PURPOSE:MDH2 (malate dehydrogenase 2) has recently been proposed as a novel potential pheochromocytoma/paraganglioma (PPGL) susceptibility gene, but its role in the disease has not been addressed. This study aimed to determine the prevalence of MDH2 pathogenic variants among PPGL patients and determine the associated phenotype. METHODS:Eight hundred thirty patients with PPGLs, negative for the main PPGL driver genes, were included in the study. Interpretation of variants of unknown significance (VUS) was performed using an algorithm based on 20 computational predictions, by implementing cell-based enzymatic and immunofluorescence assays, and/or by using a molecular dynamics simulation approach. RESULTS:Five variants with potential involvement in pathogenicity were identified: three missense (p.Arg104Gly, p.Val160Met and p.Ala256Thr), one in-frame deletion (p.Lys314del), and a splice-site variant (c.429+1G>T). All were germline and those with available biochemical data, corresponded to noradrenergic PPGL. CONCLUSION:This study suggests that MDH2 pathogenic variants may play a role in PPGL susceptibility and that they might be responsible for less than 1% of PPGLs in patients without pathogenic variants in other major PPGL driver genes, a prevalence similar to the one recently described for other PPGL genes. However, more epidemiological data are needed to recommend MDH2 testing in patients negative for other major PPGL genes.

SUBMITTER: Calsina B

PROVIDER: S-EPMC7456538 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients.

Calsina Bruna B Currás-Freixes Maria M Buffet Alexandre A Pons Tirso T Contreras Laura L Letón Rocío R Comino-Méndez Iñaki I Remacha Laura L Calatayud María M Obispo Berta B Martin Antoine A Cohen Regis R Richter Susan S Balmaña Judith J Korpershoek Esther E Rapizzi Elena E Deutschbein Timo T Vroonen Laurent L Favier Judith J de Krijger Ronald R RR Fassnacht Martin M Beuschlein Felix F Timmers Henri J HJ Eisenhofer Graeme G Mannelli Massimo M Pacak Karel K Satrústegui Jorgina J Rodríguez-Antona Cristina C Amar Laurence L Cascón Alberto A Dölker Nicole N Gimenez-Roqueplo Anne-Paule AP Robledo Mercedes M

Genetics in medicine : official journal of the American College of Medical Genetics 20180716 12

<h4>Purpose</h4>MDH2 (malate dehydrogenase 2) has recently been proposed as a novel potential pheochromocytoma/paraganglioma (PPGL) susceptibility gene, but its role in the disease has not been addressed. This study aimed to determine the prevalence of MDH2 pathogenic variants among PPGL patients and determine the associated phenotype.<h4>Methods</h4>Eight hundred thirty patients with PPGLs, negative for the main PPGL driver genes, were included in the study. Interpretation of variants of unknow ...[more]

PMID: 30008476

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Project description:BackgroundPheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.MethodsMetabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.ResultsComponents of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.ConclusionsThis study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.

Dataset Information

Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients.

Publications

Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients.

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