Data from <i>In Vivo</i> Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of <i>SDH</i>x Mutations in Paraganglioma

Abstract

<div>Abstract<p><b>Purpose:</b> 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 <i>SDHx</i>-mutated tumors. The aim of this study was to address the feasibility of detecting succinate <i>in vivo</i> by magnetic resonance spectroscopy.</p><p><b>Experimental Design:</b> A pulsed proton magnetic resonance spectroscopy (<sup>1</sup>H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with <i>Sdhb<sup>−/−</sup></i> or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (<i>n</i> = 5) or not (<i>n</i> = 4) an <i>SDHx</i> gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors.</p><p><b>Results:</b> A succinate peak was observed at 2.44 ppm by <sup>1</sup>H-MRS in all <i>Sdhb<sup>−/−</sup></i>-derived tumors in mice and in all paragangliomas of patients carrying an <i>SDHx</i> gene mutation, but neither in wild-type mouse tumors nor in patients exempt of <i>SDHx</i> mutation. In one patient, <sup>1</sup>H-MRS results led to the identification of an unsuspected <i>SDHA</i> gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the <i>SDHB</i> gene.</p><p><b>Conclusions:</b> Detection of succinate by <sup>1</sup>H-MRS is a highly specific and sensitive hallmark of <i>SDHx</i> mutations. This noninvasive approach is a simple and robust method allowing <i>in vivo</i> detection of the major biomarker of <i>SDHx</i>-mutated tumors. <i>Clin Cancer Res; 22(5); 1120–9. ©2015 AACR</i>.</p></div>