Krebs Cycle Metabolite Profiling for Identification and Stratification of Pheochromocytomas/Paragangliomas due to Succinate Dehydrogenase Deficiency

被引:111
作者
Richter, Susan [1 ]
Peitzsch, Mirko [1 ]
Rapizzi, Elena [2 ]
Lenders, Jacques W. [3 ,4 ]
Qin, Nan [1 ]
de Cubas, Aguirre A. [5 ,6 ]
Schiavi, Francesca [7 ]
Rao, Jyotsna U. [3 ]
Beuschlein, Felix [8 ]
Quinkler, Marcus [9 ]
Timmers, Henri J. [3 ]
Opocher, Giuseppe [7 ]
Mannelli, Massimo [2 ]
Pacak, Karel [10 ]
Robledo, Mercedes [5 ,6 ]
Eisenhofer, Graeme [1 ,4 ]
机构
[1] Tech Univ Dresden, Med Fac Carl Gustav Carus, Univ Hosp Carl Gustav Carus, Inst Clin Chem & Lab Med, D-01307 Dresden, Germany
[2] Univ Florence, Dept Expt & Clin Biomed Sci Mario Serio, I-50139 Florence, Italy
[3] Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6525 GA Nijmegen, Netherlands
[4] Univ Hosp Dresden, Dept Med 3, D-01307 Dresden, Germany
[5] CNIO, Hereditary Endocrine Canc Grp, Madrid, Spain
[6] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
[7] Veneto Inst Oncol IRCCS, I-35128 Padua, Italy
[8] Univ Munich, Med Klin & Poliklin 4, D-80336 Munich, Germany
[9] Univ Hosp Charite, D-10117 Berlin, Germany
[10] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA
关键词
MITOCHONDRIAL-FUNCTION; NECK PARAGANGLIOMAS; SDH MUTATIONS; 2-HYDROXYGLUTARATE; ACCUMULATION; ONCOGENESIS; DIAGNOSIS; DELETIONS; GENETICS; GLIOMAS;
D O I
10.1210/jc.2014-2151
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:3903 / 3911
页数:9
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