title: Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.M.), University of Florence and Istituto Toscano Tumori, Viale Pieraccini 6, 50139 Florence, Italy; Department of Medicine (J.W.L., J.U.R., H.J.T.), Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 8, 6525GA, Nijmegen, The Netherlands; Department of Medicine III (J.W.L., G.E.), University Hospital Dresden, Fetscherstrasse 74, 01307 Dresden, Germany; Hereditary Endocrine Cancer Group (A.A.C., M.R.), CNIO, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (A.A.C., M.R.), C/Melchor Fernández Almagro 3, 28029 Madrid, Spain; Veneto Institute of Oncology IRCCS (F.S., G.O.), Via Gattamelata 64, 35128 Padova, Italy; Medizinische Klinik and Poliklinik IV (F.B.), Ludwig-Maximilians-Universität München, Ziemssenstrasse 1, D-80336 Munich, Germany; Clinical Endocrinology (M.Q.), Campus Mitte, University Hospital Charité, Charitéplatz 1, 10117, Berlin, Germany; Eunice Kennedy Shriver National Institute of Child Health and Human Development (K.P.), National Institutes of Health, 10 Center Drive, MSC-1109, Bethesda, Maryland 20892-1109.
authors.forename: Susan
authors.initials: S
authors.lastname: Richter
authors.forename: Mirko
authors.initials: M
authors.lastname: Peitzsch
authors.forename: Elena
authors.initials: E
authors.lastname: Rapizzi
authors.forename: Jacques W
authors.initials: JW
authors.lastname: Lenders
authors.forename: Nan
authors.initials: N
authors.lastname: Qin
authors.forename: Aguirre A
authors.initials: AA
authors.lastname: de Cubas
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavi
authors.forename: Jyotsna U
authors.initials: JU
authors.lastname: Rao
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
authors.forename: Marcus
authors.initials: M
authors.lastname: Quinkler
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Timmers
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Massimo
authors.initials: M
authors.lastname: Mannelli
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000201:enzymology / Q000235:genetics*; D000328:Adult; D000368:Aged; D002952:Citric Acid Cycle / Q000235:genetics* / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D005650:Fumarates / Q000378:metabolism; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D008875:Middle Aged; D010235:Paraganglioma / Q000201:enzymology / Q000235:genetics*; D010673:Pheochromocytoma / Q000201:enzymology / Q000235:genetics*; D012680:Sensitivity and Specificity; D013385:Succinate Dehydrogenase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism; D055815:Young Adult
chemical_list: D005650:Fumarates; D019802:Succinic Acid; D013385:Succinate Dehydrogenase