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In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

By Charlotte Lussey-Lepoutre, Alexandre Bellucci, Aur Elie Morin, Alexandre Buffet, Laurence Amar, Maxime Janin, Chris Ottolenghi, Franck Zinzindohou, Gwennhael Autret, Nelly Burnichon, Estelle Robidel, Benjamin Banting, Sébastien Fontaine, Charles-André Cuenod, Paule Benit, Pierre Rustin, Philippe Halimi, Laure Fournier, Anne-Paule Gimenez-Roqueplo, Judith Favier and Bertrand Tavitian

Abstract

International audiencePurpose: Germline mutations in genes encoding mitochon-drial 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. Experimental Design: A pulsed proton magnetic resonance spectroscopy (1 H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb À/À or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n ¼ 5) or not (n ¼ 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 À/À-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 unsus-pected 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 non-invasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. Clin Cancer Res; 22(5); 1120–9. Ó2015 AACR

Topics: [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology
Publisher: American Association for Cancer Research
Year: 2015
DOI identifier: 10.1158/1078-0432.CCR-15-1576
OAI identifier: oai:HAL:inserm-01315810v1
Provided by: Hal-Diderot

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