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Metabolome-guided genomics to identify mutations in isocitrate dehydrogenase, fumarate hydratase and succinate dehydrogenase genes in pheochromocytoma and paraganglioma

PURPOSE: Metabolic aberrations have been described in neoplasms with mutations in the Krebs cycle genes encoding succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH). In turn, accumulation of oncometabolites succinate, fumarate, and 2-hydroxyglutarate can be empl...

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Autores principales: Richter, Susan, Gieldon, Laura, Pang, Ying, Peitzsch, Mirko, Huynh, Thanh, Leton, Rocio, Viana, Bruna, Ercolino, Tonino, Mangelis, Anastasios, Rapizzi, Elena, Menschikowski, Mario, Aust, Daniela, Kroiss, Matthias, Beuschlein, Felix, Gudziol, Volker, Timmers, Henri JLM, Lenders, Jacques, Mannelli, Massimo, Cascon, Alberto, Pacak, Karel, Robledo, Mercedes, Eisenhofer, Graeme, Klink, Barbara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353556/
https://www.ncbi.nlm.nih.gov/pubmed/30050099
http://dx.doi.org/10.1038/s41436-018-0106-5
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author Richter, Susan
Gieldon, Laura
Pang, Ying
Peitzsch, Mirko
Huynh, Thanh
Leton, Rocio
Viana, Bruna
Ercolino, Tonino
Mangelis, Anastasios
Rapizzi, Elena
Menschikowski, Mario
Aust, Daniela
Kroiss, Matthias
Beuschlein, Felix
Gudziol, Volker
Timmers, Henri JLM
Lenders, Jacques
Mannelli, Massimo
Cascon, Alberto
Pacak, Karel
Robledo, Mercedes
Eisenhofer, Graeme
Klink, Barbara
author_facet Richter, Susan
Gieldon, Laura
Pang, Ying
Peitzsch, Mirko
Huynh, Thanh
Leton, Rocio
Viana, Bruna
Ercolino, Tonino
Mangelis, Anastasios
Rapizzi, Elena
Menschikowski, Mario
Aust, Daniela
Kroiss, Matthias
Beuschlein, Felix
Gudziol, Volker
Timmers, Henri JLM
Lenders, Jacques
Mannelli, Massimo
Cascon, Alberto
Pacak, Karel
Robledo, Mercedes
Eisenhofer, Graeme
Klink, Barbara
author_sort Richter, Susan
collection PubMed
description PURPOSE: Metabolic aberrations have been described in neoplasms with mutations in the Krebs cycle genes encoding succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH). In turn, accumulation of oncometabolites succinate, fumarate, and 2-hydroxyglutarate can be employed to identify tumors with those mutations. Additionally, such metabolic readouts may aid in genetic variant interpretation and improve diagnostics. METHODS: Using liquid-chromatography-mass-spectrometry, 395 pheochromocytomas and paragangliomas (PPGLs) from 391 patients were screened for metabolites to indicate Krebs cycle aberrations. Multi-gene panel-sequencing was applied to detect driver mutations in cases with indicative metabolite profiles but undetermined genetic drivers. RESULTS: Aberrant Krebs cycle metabolomes identified rare cases of PPGLs with germline mutations in FH and somatic mutations in IDHx and SDHx, including the first case of a somatic IDH2 mutation in PPGL. Metabolomics also reliably identified PPGLs with SDHx loss-of-function (LOF) mutations. Therefore we utilized tumor metabolite profiles to further classify variants of unknown significance in SDHx, thereby enabling missense-variants associated with SDHx LOF to be distinguished from benign variants. CONCLUSION: We propose incorporation of metabolome data into the diagnostics algorithm in PPGLs to guide genetic testing and variant interpretation and to help identify rare cases with mutations in FH and IDHx.
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spelling pubmed-63535562019-03-07 Metabolome-guided genomics to identify mutations in isocitrate dehydrogenase, fumarate hydratase and succinate dehydrogenase genes in pheochromocytoma and paraganglioma Richter, Susan Gieldon, Laura Pang, Ying Peitzsch, Mirko Huynh, Thanh Leton, Rocio Viana, Bruna Ercolino, Tonino Mangelis, Anastasios Rapizzi, Elena Menschikowski, Mario Aust, Daniela Kroiss, Matthias Beuschlein, Felix Gudziol, Volker Timmers, Henri JLM Lenders, Jacques Mannelli, Massimo Cascon, Alberto Pacak, Karel Robledo, Mercedes Eisenhofer, Graeme Klink, Barbara Genet Med Article PURPOSE: Metabolic aberrations have been described in neoplasms with mutations in the Krebs cycle genes encoding succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH). In turn, accumulation of oncometabolites succinate, fumarate, and 2-hydroxyglutarate can be employed to identify tumors with those mutations. Additionally, such metabolic readouts may aid in genetic variant interpretation and improve diagnostics. METHODS: Using liquid-chromatography-mass-spectrometry, 395 pheochromocytomas and paragangliomas (PPGLs) from 391 patients were screened for metabolites to indicate Krebs cycle aberrations. Multi-gene panel-sequencing was applied to detect driver mutations in cases with indicative metabolite profiles but undetermined genetic drivers. RESULTS: Aberrant Krebs cycle metabolomes identified rare cases of PPGLs with germline mutations in FH and somatic mutations in IDHx and SDHx, including the first case of a somatic IDH2 mutation in PPGL. Metabolomics also reliably identified PPGLs with SDHx loss-of-function (LOF) mutations. Therefore we utilized tumor metabolite profiles to further classify variants of unknown significance in SDHx, thereby enabling missense-variants associated with SDHx LOF to be distinguished from benign variants. CONCLUSION: We propose incorporation of metabolome data into the diagnostics algorithm in PPGLs to guide genetic testing and variant interpretation and to help identify rare cases with mutations in FH and IDHx. 2018-07-27 2019-03 /pmc/articles/PMC6353556/ /pubmed/30050099 http://dx.doi.org/10.1038/s41436-018-0106-5 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Richter, Susan
Gieldon, Laura
Pang, Ying
Peitzsch, Mirko
Huynh, Thanh
Leton, Rocio
Viana, Bruna
Ercolino, Tonino
Mangelis, Anastasios
Rapizzi, Elena
Menschikowski, Mario
Aust, Daniela
Kroiss, Matthias
Beuschlein, Felix
Gudziol, Volker
Timmers, Henri JLM
Lenders, Jacques
Mannelli, Massimo
Cascon, Alberto
Pacak, Karel
Robledo, Mercedes
Eisenhofer, Graeme
Klink, Barbara
Metabolome-guided genomics to identify mutations in isocitrate dehydrogenase, fumarate hydratase and succinate dehydrogenase genes in pheochromocytoma and paraganglioma
title Metabolome-guided genomics to identify mutations in isocitrate dehydrogenase, fumarate hydratase and succinate dehydrogenase genes in pheochromocytoma and paraganglioma
title_full Metabolome-guided genomics to identify mutations in isocitrate dehydrogenase, fumarate hydratase and succinate dehydrogenase genes in pheochromocytoma and paraganglioma
title_fullStr Metabolome-guided genomics to identify mutations in isocitrate dehydrogenase, fumarate hydratase and succinate dehydrogenase genes in pheochromocytoma and paraganglioma
title_full_unstemmed Metabolome-guided genomics to identify mutations in isocitrate dehydrogenase, fumarate hydratase and succinate dehydrogenase genes in pheochromocytoma and paraganglioma
title_short Metabolome-guided genomics to identify mutations in isocitrate dehydrogenase, fumarate hydratase and succinate dehydrogenase genes in pheochromocytoma and paraganglioma
title_sort metabolome-guided genomics to identify mutations in isocitrate dehydrogenase, fumarate hydratase and succinate dehydrogenase genes in pheochromocytoma and paraganglioma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353556/
https://www.ncbi.nlm.nih.gov/pubmed/30050099
http://dx.doi.org/10.1038/s41436-018-0106-5
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