Pheochromocytoma: A Genetic and Diagnostic Update

Leilani B. Mercado-Asis, MD, PhD, MPH; Katherine I. Wolf; Ivana Jochmanova, MD; David Taïeb, MD


Endocr Pract. 2018;24(1):78-90. 

In This Article

Metabolomics and Pheochromocytoma

PPGL susceptibility gene mutations result in the dysregulation of cellular key metabolic pathways and subsequent tumorigenic transformation. A metabolic change in transformed cells promotes increased biosynthesis of macromolecules needed for tumor growth and shifts cell metabolism from oxidative phosphorylation to aerobic glycolysis.[31]

Measurements of the Krebs cycle and other metabolites in PPGLs confirmed the role of succinate and fuma-rate in tumorigenesis (Figure 1).[32–35] At high levels, both succinate and fumarate act as competitive inhibitors of α-ketoglutarate-dependent dioxygenases, including HIF prolyl hydroxylases (PHDs), needed for HIF-α proteasomal degradation (reviewed in[18]). Hence, high levels of succinate and fumarate lead to the activation of the hypoxia signaling pathway and all metabolic consequences, including activation of protumorigenic mechanisms.[31,36]

Figure 1.

Metabolic changes and tumorigenesis in PPGL. Schematic representation of mitochondrial genes involved in PHEO development with emphasis to the Krebs cycle enzymes and candidate genes (red) (See Figure 2) and possible areas for therapeutic targets (see Table 3). Dotted lines result from mutations of genes or proteins (red). SDHB has been shown to have the abnormal metabolic characteristics. α-KGDH = alpha-ketoglutarate dehydrogenase; ACO = aconitase; CoA = coenzyme A; COMT = catechol-O-methyl transferase; CS = citrate synthase, c-MYC = MYC proto oncognene; elF-4E = eukaryotic initiation factor 4E; EMT = epithelial-to-mesenchymal transition; ERK = extracellular signal-regulated kinase; FH = fumarate hydroxylase; HIF-α = hypoxia-inducible factor alpha; IDH = isocitrate dehydrogenase; MDH2 = malate dehydrogenase; mTORC1 = mammalian target of rapamycin complex 1; PDH = pyruvate dehydrogenase; PHD = prolyl hydroxylase domain protein; PPGL = pheochromocytomas and paragangliomas; pVHL = von Hippel-Lindau protein; Raptor = regulatory associated protein of mTOR; RAS = rat sarcoma oncogene; RET = rearranged during transfection proto-oncogene; ROS = reactive oxygen species; S6K = S6 kinase; SDH = succinate dehydrogenase; SUCLG = succinyl-CoA synthase; TMEM127 = transmembrane protein 127 (partially adapted from (31, 35).

SDHx mutations in PPGLs result in the accumulation of succinate, increased levels of methionine, glutamine, and myoinositol, as well as decreased levels of fumarate, glutamate, citrate, isocitrate, and several other metabolites (Figure 1 and Figure 2).[34,35] A high succinate-to-fumarate ratio helps discriminate between PPGLs with and without SDHx mutations.[33,34] Moreover, simultaneous measurement of all mentioned metabolites discriminates SDHx from non-SDHx tumors, with 100% sensitivity and specificity. This is important for patients with SDHx-related tumors who present with low catecholamine secretion or biochemically silent disease. SDHx tumors (particularly SDHB) display more aggressive behavior and have a high meta-static potential.[37]

Figure 2.

Whole tumoral metabolome (A) and 3-component OPLS-DA model (B) in SDHx versus sporadic pheochromocytoma. Note that SDHx tumors have a higher succinate, taurine, and myoinositol metabolic fingerprint. Ad = adenine; GSH = glutathione; NAd = nicotinamide-adenine dinucleotide; OPLS-DA = orthogonal partial least square discriminant analysis (32).

Accumulation of fumarate in FH- and MDH2-mutated PPGLs promotes oncogenesis through the succination of proteins, an irreversible covalent bond of fumarate to cysteine residues.[38–40] Additionally, succinate/fumarate accumulation results in hypermethylated phenotype in SDHx- and FH-mutated tumors due to inhibition of ten-eleven-translocation methylcytosine dioxygenase (TET).[41,42] These findings emphasize the interconnection between the Krebs cycle and epigenomic changes.[31]

Decreased levels of Krebs cycle intermediates, specifically citrate, isocitrate, and cis-aconitate, detected in SDHx- and VHL-related PPGLs are also associated with epigenetic and metabolic changes participating in oncogenic processes. Citrate can switch between metabolic pathways and is also used for synthesis of pyruvate, fatty acids, and sterols. Decreased citrate levels have been linked to the induction of epithelial-to-mesenchymal transition, and thus, cancer cell invasion and metastasis.[43]

Metabolomic studies conducted on PPGLs revealed other interesting findings. SDHx-mutated tumors displayed a lower activity of the SDH enzyme (complex II of electron transport chain) but increased activities of complexes I, III, and IV of the electron transport chain. However, the increased activities of the remaining complexes did not lead to full restoration of normal function.[44] High levels of glutamine, the second most abundant nutrient in cancer cells, in SDHx-related PPGLs suggest that glutamine metabolism is involved in the pathogenesis of these tumors.[35] The differences in catecholamine synthesis and secretion among PPGLs with different genetic backgrounds can also be explained based on the metabolic changes resulting from a particular mutation, specifically by mutation-dependent changes in energy metabolism.[44] In PPGLs, ascorbate, a cofactor in the conversion of dopamine to norepinephrine, accumulates. Levels of ascorbate correlate with catecholamine concentrations.[35] Interestingly, ATP production is not impaired in SDH-deficient PPGLs, implying that the Krebs cycle and oxidative phosphorylation function together with aerobic glycolysis in these tumors.[31,35]

Based on the available data, PPGLs are very heterogeneous tumors and exhibit diverse metabolic changes and specific metabolic signatures. Further understanding of PPGL metabolism will help us to improve diagnostic and therapeutic methods.