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J Clin Endocrinol Metab. 2015 Feb;100(2):E214-22. doi: 10.1210/jc.2014-2138. Epub 2014 Dec 2.

Genotype-specific differences in the tumor metabolite profile of pheochromocytoma and paraganglioma using untargeted and targeted metabolomics.

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Department of Laboratory Medicine, Laboratory of Genetic, Endocrine and Metabolic Diseases (J.U.R., U.F.H., F.C.G.J., A.G.G., R.A.W.), Department of Internal Medicine, Section of Endocrinology (J.U.R., H.J.L.M.T., A.R.M.M.H.), Radboud University Medical Centre, Nijmegen, The Netherlands; Eunice Kennedy Shriver National Institute of Child Health and Human Development (K.P.), National Institute of Health, Bethesda, Maryland 20892; Department of Pathology (B.K.), Department of Genetics (A.R.M.), Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Medicine and Institute of Clinical Chemistry & Laboratory Medicine (G.E., N.Q., S.R.), University Hospital Carl Gustav Carus, Dresden, Germany; Department of Otolaryngology (H.P.M.K.), Radboud University Medical Centre, Nijmegen, The Netherlands; and Department of Pathology (B.K.), Maastricht University Medical Centre, Maastricht, The Netherlands.



Pheochromocytomas and paragangliomas (PGLs) are neuroendocrine tumors of sympathetic or parasympathetic paraganglia. Nearly 40% of PGLs are caused by germline mutations. The present study investigated the effect of genetic alterations on metabolic networks in PGLs.


Homogenates of 32 sporadic PGLs and 48 PGLs from patients with mutations in SDHB, SDHD, SDHAF-2, VHL, RET, and NF-1 were subjected to proton ((1)H) nuclear magnetic resonance (NMR) spectroscopy at 500 MHz for untargeted and HPLC tandem mass spectrometry for targeted metabolite profiling.


(1)H NMR spectroscopy identified 28 metabolites in PGLs of which 12 showed genotype-specific differences. Part of these results published earlier reported low complex II activity (P < .0001) and low ATP/ADP/AMP content (P < .001) in SDH-related PGLs compared with sporadics and PGLs of other genotypes. Extending these results, low levels of N-acetylaspartic acid (NAA; P < .05) in SDH tumors and creatine (P < .05) in VHL tumors were observed compared with sporadics and other genotypes. Positive correlation was observed between NAA and ATP/ADP/AMP content (P < .001) and NAA and complex II activity (P < .0001) of PGLs. Targeted purine analysis in PGLs showed low adenine in cluster 1 compared with cluster 2 tumors (SDH P < .0001; VHL P < .05) whereas lower levels (P < .05) of guanosine and hypoxanthine were observed in RET tumors compared with SDH tumors. Principal component analysis (PCA) of metabolites could distinguish PGLs of different genotypes.


The present study gives a comprehensive picture of alterations in energy metabolism in SDH- and VHL-related PGLs and establishes the interrelationship of energy metabolism and amino acid and purine metabolism in PGLs.

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