In vivo detection of succinate by magnetic resonance spectroscopy as a hallmark of SDHx mutations in paraganglioma
Menée à l'aide de modèles murins et sur 9 patients atteints d'un paragangliome, cette étude française met en évidence l'intérêt de la détection non invasive de succinate pour identifier des tumeurs présentant des mutations de gènes codant la succinate déshydrogénase mitochondriale
Purpose : 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.
Experimental design : A pulse proton magnetic resonance spectroscopy (1H-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 paraganglioma patients 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 1H-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, 1H-MRS results led to the identification of an unsuspected SDHA gene mutation. In another case, it helped defining the pathogenicity of a variant of unknown significance in the SDHB gene.
Conclusions : Detection of succinate by 1H-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 SDH-mutated tumors.
Clinical Cancer Research , résumé, 2015