Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma.
2-hydroxyglutarate
fumarate
next-generation sequencing
succinate
variant of unknown significance
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
29
01
2018
accepted:
18
06
2018
pubmed:
28
7
2018
medline:
16
7
2019
entrez:
28
7
2018
Statut:
ppublish
Résumé
Metabolic aberrations have been described in neoplasms with pathogenic variants (PV) 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 PV . Additionally, such metabolic readouts may aid in genetic variant interpretation and improve diagnostics. Using liquid chromatography-mass spectrometry, 395 pheochromocytomas and paragangliomas (PPGLs) from 391 patients were screened for metabolites to indicate Krebs cycle aberrations. Multigene panel sequencing was applied to detect driver PV in cases with indicative metabolite profiles but undetermined genetic drivers. Aberrant Krebs cycle metabolomes identified rare cases of PPGLs with germline PV in FH and somatic PV in IDHx and SDHx, including the first case of a somatic IDH2 PV in PPGL. Metabolomics also reliably identified PPGLs with SDHx loss-of-function (LOF) PV. 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. 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 PV in FH and IDHx.
Identifiants
pubmed: 30050099
doi: 10.1038/s41436-018-0106-5
pii: S1098-3600(21)01032-7
pmc: PMC6353556
mid: NIHMS1505462
doi:
Substances chimiques
Isocitrate Dehydrogenase
EC 1.1.1.41
Succinate Dehydrogenase
EC 1.3.99.1
Fumarate Hydratase
EC 4.2.1.2
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
705-717Subventions
Organisme : Intramural NIH HHS
ID : ZIA HD008735-16
Pays : United States
Organisme : NIH HHS
ID : ZIA HD008735-16
Pays : United States
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