Exp Clin Endocrinol Diabetes 2014; 122 - OP6_30
DOI: 10.1055/s-0034-1372005

Identification and stratification of pheochromocytomas/paragangliomas with SDHx mutations using the succinate to fumarate ratio

S Richter 1, M Peitzsch 1, E Rapizzi 2, JW Lenders 3, 4, N Qin 1, AA de Cubas 5, F Schiavi 6, JU Rao 3, F Beuschlein 7, M Quinkler 8, HJ Timmers 3, G Opocher 6, M Mannelli 2, K Pacak 9, M Robledo 5, G Eisenhofer 1, 4
  • 1Dresden University of Technology/University Hospital Dresden, Department of Clinical Chemistry and Laboratory Medicine, Dresden, Germany
  • 2University of Florence/Istituto Toscano Tumori, Department of Clinical Pathophysiology, Florence, Italy
  • 3Radboud University Nijmegen Medical Centre, Nijmegen, Department of Medicine, Nijmegen, Netherlands
  • 4Dresden University of Technology/University Hospital Dresden, Department of Medicine III, Dresden, Germany
  • 5CNIO Madrid, Hereditary Endocrine Cancer Group, Madrid, Spain
  • 6Veneto Institute of Oncology IRCCS Padova, Padova, Italy
  • 7Ludwig-Maximilians-Universität München, Medizinische Klinik and Poliklinik IV, Munich, Germany
  • 8University Hospital Charité Berlin, Clinical Endocrinology, Berlin, Germany
  • 9National Institutes of Health, Bethesda, United States

Mutations in succinate dehydrogenase (SDH) genes are responsible for cancer formation in certain tumors, including in pheochromocytomas and paragangliomas (PPGLs). Especially mutations in SDH subunit B result in tumors with immature phenotypic features of low catecholamine contents, significant production of dopamine, and high prevalence to metastases.

The present study evaluates the succinate: fumarate ratio (SFR) as a new biomarker for identification of SDHx mutations in PPGLs and also assesses changes in the metabolome more broadly.

Tumor tissue metabolites (including most Krebs cycle intermediates, pyruvate and lactate) of 234 PPGLs were measured by LC-MS/MS. Among our patient cohort, 45 had confirmed germline mutations in SDHB, SDHC or SDHD. A subset of samples (50) formed a training set and the majority (184) was analysed blind to the mutational status in a validation series. Predictions about the presence of SDHx mutations were provided based on the SFR.

Median SFRs in tumors from patients with SDHx germline mutations were dramatically increased by 454-fold in the training and 94-fold in the validation set above tumors without SDHx mutations. Succinate was elevated 25-fold in tumors of patients with SDHx germline mutations, whereas fumarate, citrate, cis-aconitate and isocitrate were respectively decreased by 80%, 60%, 82%, and 80%. The diagnostic performance of the SFR as a sole predictor for SDHx mutations was estimated at 97% specificity and 93% sensitivity. With exclusion of head and neck paragangliomas sensitivity reached 100%. Among patients with SDHx mutations, higher SFRs were measured in tumors due to SDHB mutations or associated with metastatic disease than in those due to SDHC or SDHD mutations or without metastatic disease.

The SFR of PPGLs predicts the presence of SDHx mutations with high diagnostic performance, and may also be useful for assessing metabolic factors responsible for malignant risk and responses to various treatment options.