In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma.
OBJECTIVE
Germline mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy.


METHODS
A pulsed proton magnetic resonance spectroscopy ((1)H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb(-/-) or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n = 5) or not (n = 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors.


RESULTS
A succinate peak was observed at 2.44 ppm by (1)H-MRS in all Sdhb(-/-)-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, (1)H-MRS results led to the identification of an unsuspected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene.


CONCLUSIONS
Detection of succinate by (1)H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This noninvasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors.
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Charlotte
C
Lussey-Lepoutre
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Alexandre
A
Bellucci
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Aurélie
A
Morin
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Alexandre
A
Buffet
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'hypertension artérielle et médecine vasculaire, Paris, France.
Laurence
L
Amar
Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Laboratoire de Biochimie Métabolique, Paris, France. INSERM, U1124, Paris, France.
Maxime
M
Janin
Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Laboratoire de Biochimie Métabolique, Paris, France. INSERM, U1124, Paris, France.
Chris
C
Ottolenghi
Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Chirurgie Digestive, Paris, France.
Franck
F
Zinzindohoué
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Gwennhael
G
Autret
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France.
Nelly
N
Burnichon
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Estelle
E
Robidel
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France.
Benjamin
B
Banting
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France.
Sébastien
S
Fontaine
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France.
Charles-André
CA
Cuenod
INSERM, UMR1141, Hôpital Robert Debré, Paris, France. Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France.
Paule
P
Benit
INSERM, UMR1141, Hôpital Robert Debré, Paris, France. Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France.
Pierre
P
Rustin
Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France.
Philippe
P
Halimi
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France.
Laure
L
Fournier
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France.
Anne-Paule
AP
Gimenez-Roqueplo
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. judith.favier@inserm.fr.
Judith
J
Favier
INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France.
Bertrand
B
Tavitian
D000818:Animals; D042963:Electron Transport Complex II / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000235:genetics*; D019802:Succinic Acid / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D008565:Membrane Proteins; C108096:SDHC protein, human; C491545:SDHD protein, human; D019802:Succinic Acid; D042963:Electron Transport Complex II; C511268:SDHA protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase