Krebs Cycle Metabolite Profiling for Identification and Stratification of Pheochromocytomas/Paragangliomas due to Succinate Dehydrogenase Deficiency
Krebs Cycle Metabolite Profiling for Identification and Stratification of Pheochromocytomas/Paragangliomas due to Succinate Dehydrogenase Deficiency
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DOI：
10.1210/jc.2014-2151
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发表时间：
2014-10-01
影响因子：
5.8
通讯作者：
Eisenhofer, Graeme
中科院分区：
文献类型：
--
作者：
Richter, Susan;Peitzsch, Mirko;Eisenhofer, Graeme
内容：琥珀酸脱氢酶A/B/C/D基因（SDHx）的突变增加了嗜铬细胞瘤和副神经节瘤（PPGL）的易感性，特别是与SDHB突变相关的恶性肿瘤发生率高。目的：我们评估了琥珀酸脱氢酶产物-前体关系的改变，表现为琥珀酸与富马酸或其他代谢物的肿瘤比率的差异，可能有助于SDHx突变患者的识别和分层。设计、设置和患者：来自233名患者的PPGL肿瘤标本，包括45名SDHx突变患者，由八个三级转诊中心提供，用于克雷布斯循环代谢物的质谱分析。主要结果指标：琥珀酸盐的诊断性能：结果：与没有SDHx突变的PPGL相比，SDH缺陷型PPGL的特征在于琥珀酸水平高25倍，富马酸、顺乌头酸和异柠檬酸组织水平低80%。使用琥珀酸盐与富马酸盐或顺乌头酸盐和异柠檬酸盐的比值识别SDHX突变的受试者工作特征曲线表明曲线下面积为0.94至0.96;琥珀酸盐：富马酸盐比值的最佳截止值为97.7，诊断灵敏度为93%，特异性为97%，以识别SDHX突变的PPGL。琥珀酸盐：富马酸盐比率在SDHB突变和转移性肿瘤中均高于那些由于SDHD/C突变或无metastasis.Conclusions：基于质谱的琥珀酸盐：富马酸盐和PPGL中其他代谢物比率的测量提供了一种有用的方法来识别患者以测试SDHX突变，并具有额外的实用性，以定量评估突变和代谢因素的功能，负责恶性风险。
Context: Mutations of succinate dehydrogenase A/B/C/D genes (SDHx) increase susceptibility to development of pheochromocytomas and paragangliomas (PPGLs), with particularly high rates of malignancy associated with SDHB mutations.Objective: We assessed whether altered succinate dehydrogenase product-precursor relationships, manifested by differences in tumor ratios of succinate to fumarate or other metabolites, might aid in identifying and stratifying patients with SDHx mutations.Design, Setting, and Patients: PPGL tumor specimens from 233 patients, including 45 with SDHx mutations, were provided from eight tertiary referral centers for mass spectrometric analyses of Krebs cycle metabolites.Main Outcome Measure: Diagnostic performance of the succinate: fumarate ratio for identification of pathogenic SDHx mutations.Results: SDH-deficient PPGLs were characterized by 25-fold higher succinate and 80% lower fumarate, cis-aconitate, and isocitrate tissue levels than PPGLs without SDHx mutations. Receiver-operating characteristic curves for use of ratios of succinate to fumarate or to cis-aconitate and isocitrate to identify SDHx mutations indicated areas under curves of 0.94 to 0.96; an optimal cut-off of 97.7 for the succinate: fumarate ratio provided a diagnostic sensitivity of 93% at a specificity of 97% to identify SDHX-mutated PPGLs. Succinate: fumarate ratios were higher in both SDHB-mutated and metastatic tumors than in those due to SDHD/C mutations or without metastases.Conclusions: Mass spectrometric-based measurements of ratios of succinate: fumarate and other metabolites in PPGLs offer a useful method to identify patients for testing of SDHx mutations, with additional utility to quantitatively assess functionality of mutations and metabolic factors responsible for malignant risk.