Pheochromocytoma/Paraganglioma: A Poster Child for Cancer Metabolism

Pheochromocytoma/Paraganglioma: A Poster Child for Cancer Metabolism Abstract Context Pheochromocytomas (PCCs) are tumors that are derived from the chromaffin cells of the adrenal medulla. Extra-adrenal PCCs called paragangliomas (PGLs) are derived from the sympathetic and parasympathetic chain ganglia. PCCs secrete catecholamines, which cause hypertension and have adverse cardiovascular consequences as a result of catecholamine excess. PGLs may or may not produce catecholamines depending on their genetic type and anatomical location. The most worrisome aspect of these tumors is their ability to become aggressive and metastasize; there are no known cures for metastasized PGLs. Methods Original articles and reviews indexed in PubMed were identified by querying with specific PCC/PGL- and Krebs cycle pathway–related terms. Additional references were selected through the in-depth analysis of the relevant publications. Results We primarily discuss Krebs cycle mutations that can be instrumental in helping investigators identify key biological pathways and molecules that may serve as biomarkers of or treatment targets for PCC/PGL. Conclusion The mainstay of treatment of patients with PCC/PGLs is surgical. However, the tide may be turning with the discovery of new genes associated with PCC/PGLs that may shed light on oncometabolites used by these tumors. In 1886, the year that Robert Louis Stevenson published his novel Strange Case of Dr. Jekyll and Mr. Hyde, the first case of pheochromocytoma (PCC) was documented in Germany and described an 18-year-old woman with hypertensive crisis due to bilateral adrenal tumors (1). A quarter century later, the German pathologist Ludwig Pick noted a color change after adding chromium salts to adrenal medullary tumors. He coined the term pheochromocytoma from the Greek “phaios” (dark), “chroma” (color), and “cytoma” (tumor) (2). Over the years, PCC and paraganglioma (PGL) tumors have revealed, like the main character in Stevenson’s novel, their “split personality” in presentation and behavior (3), as well as in different genetic origins. The clues as to what has been hiding behind the changes come from Dr. Otto Warburg’s insightful observation that tumorogenic cells use glucose at higher levels compared with normal cells (4). Warburg went on to propose that this difference in metabolism is the fundamental cause of cancer. A better understanding of glucose metabolism came through the discovery of the tricarboxylic acid (TCA) cycle, or Krebs cycle, by Warburg’s mentee, Dr. Hans Krebs. By 1937, the TCA cycle was thoroughly described and provided the foundation of our understanding of cell metabolism. However, the connection between deficient Krebs cycle and cancer only became uncovered in the 21st century, when mutations were found in the succinate dehydrogenase subunits (SDHx) complex in hereditary PCC/PGLs. This discovery became the first documented case that directly linked defective mitochondrial protein with cancer predisposition (5). PCC/PGL: Where Are We Now? The initial diagnosis of PCC/PGL is usually made by inspecting plasma metanephrines or 24-hour urine for catecholamines and metanephrines (6, 7). After the biochemical evaluation, imaging studies such as computed tomography scans or magnetic resonance imaging studies are routinely conducted. To evaluate the extent of possible metastatic disease, the metaiodobenzylguanidine scan, for which a radiolabeled compound is taken up by PCC/PGL cells, traditionally is used to determine the tumor location. However, studies have reported better sensitivity for the fluorodeoxyglucose positron emission tomography approach to identify aggressive PCC/PGL disease (8). Recent research is recognizing 68Ga-labeled somatostatin analogs (DOTATATE) as a promising modality in finding PCC/PGL disease (9). This advancement in PCC/PGL imaging has come about through understanding of the alteration in glucose metabolism in these tumors (10). The mainstay of PCC/PGL treatment is surgical, because there are no medical therapies for metastatic disease and it is estimated that a median overall survival rate for patients with specific mutations is about 3 years (11). Even when a primary tumor is removed, a pathologist is not able to tell if the tumor is malignant or benign. The determination of metastatic disease is made when the patient’s imaging results are consistent with metastatic disease. Clues to whether the patient may have metastatic disease have come with the understanding of new genes associated with malignant behavior, which is discussed later in this review. Gene Clusters in PCC/PGLs We now know that there are 21 genes associated with PCC/PGLs—more than any number of genes associated with any other endocrine tumor (12) (Table 1). A few years before the discovery of mutations in the SDHx complex, genes associated with PCC syndromes were isolated, such as neurofibromatosis type 1 and rearranged during transfection (RET) proto-oncogene, which is associated with multiple endocrine neoplasia 2 syndrome. How these different genes cause PCC/PGLs has been an area of intense investigation. Table 1. Genes With Known Mutations in the PCC/PGL Tumors Gene Name Known Mutation Reference ATRX Loss of function (13, 14) CSDE1 Loss of function (15) FH Loss of function (16) HIF2A Gain of function (17–19) HRAS Gain of function (20) IDH1 Gain of function (21) KIF1B Loss of function (22) MAML3 Gain of function (15) MAX Loss of function (23) MDH2 Loss of function (24) MEN2 (RET) Gain of function (25, 26) NF1 Loss of function (27, 28) PHD1 (EGLN2) Loss of function (29) PHD2 (EGLN1) Loss of function (30) SDHA Loss of function (31) SDHAF2 Loss of function (32) SDHB Loss of function (33) SDHC Loss of function (34) SDHD Loss of function (5) TMEM127 Loss of function (35) VHL Loss of function (36) Gene Name Known Mutation Reference ATRX Loss of function (13, 14) CSDE1 Loss of function (15) FH Loss of function (16) HIF2A Gain of function (17–19) HRAS Gain of function (20) IDH1 Gain of function (21) KIF1B Loss of function (22) MAML3 Gain of function (15) MAX Loss of function (23) MDH2 Loss of function (24) MEN2 (RET) Gain of function (25, 26) NF1 Loss of function (27, 28) PHD1 (EGLN2) Loss of function (29) PHD2 (EGLN1) Loss of function (30) SDHA Loss of function (31) SDHAF2 Loss of function (32) SDHB Loss of function (33) SDHC Loss of function (34) SDHD Loss of function (5) TMEM127 Loss of function (35) VHL Loss of function (36) View Large Table 1. Genes With Known Mutations in the PCC/PGL Tumors Gene Name Known Mutation Reference ATRX Loss of function (13, 14) CSDE1 Loss of function (15) FH Loss of function (16) HIF2A Gain of function (17–19) HRAS Gain of function (20) IDH1 Gain of function (21) KIF1B Loss of function (22) MAML3 Gain of function (15) MAX Loss of function (23) MDH2 Loss of function (24) MEN2 (RET) Gain of function (25, 26) NF1 Loss of function (27, 28) PHD1 (EGLN2) Loss of function (29) PHD2 (EGLN1) Loss of function (30) SDHA Loss of function (31) SDHAF2 Loss of function (32) SDHB Loss of function (33) SDHC Loss of function (34) SDHD Loss of function (5) TMEM127 Loss of function (35) VHL Loss of function (36) Gene Name Known Mutation Reference ATRX Loss of function (13, 14) CSDE1 Loss of function (15) FH Loss of function (16) HIF2A Gain of function (17–19) HRAS Gain of function (20) IDH1 Gain of function (21) KIF1B Loss of function (22) MAML3 Gain of function (15) MAX Loss of function (23) MDH2 Loss of function (24) MEN2 (RET) Gain of function (25, 26) NF1 Loss of function (27, 28) PHD1 (EGLN2) Loss of function (29) PHD2 (EGLN1) Loss of function (30) SDHA Loss of function (31) SDHAF2 Loss of function (32) SDHB Loss of function (33) SDHC Loss of function (34) SDHD Loss of function (5) TMEM127 Loss of function (35) VHL Loss of function (36) View Large Depending on the type of the mutation, PCC/PGLs have distinctive gene expression profiles that assemble (cluster) in two so-called cluster groups (37, 38). Mutations affecting Von Hippel Lindau (VHL) protein and subunits of the succinate dehydrogenase (SDH) complex or SDH accessory proteins (i.e., SDHA, SDHB, SDHC, SDHD, and SDHAF2) and, rarely, isocitrate dehydrogenase (IDH) mutations, are among the causes of PCC/PGLs that make up cluster 1 tumors that are noradrenergic (37, 38). Most of the tumors that comprise cluster 1 are PGLs (37, 38). Their noradrenergic nature likely stems from the hypermethylation of the phenylethanolamine N-methyltransferase (PNMT) gene and subsequent lack of norepinephrine to epinephrine conversion. The proposed molecular mechanism involves inhibition of 2-oxoglutarate–dependent histone demethylases (39). Neurofibromatosis type 1, transmembrane protein 127 and multiple endocrine neoplasma type 2 due to mutations of the RET gene are well-established causes of hereditary PCC/PGLs; these tumors constitute cluster 2 (40, 41). Interestingly, DNA from the four living relatives of the first PCC/PGL patient described in 1886 demonstrated the presence of a germ-line RET mutation (1). Recently, The Cancer Genome Atlas Program verified the genetic composition of cluster 1 and cluster 2 tumors (15). Most gene mutations giving rise to the noradrenergic cluster 1 phenotype are primarily associated with Krebs cycle enzyme mutations as well as the pseudohypoxia pathway. In contrast, mutations in cluster 2 genes are found in tumors with adrenergic phenotype. This comprehensive project also uncovered two additional gene expression clusters (15). The third cluster is associated with an expression of the Mastermind-like 3 (MAML3)–fusion genes and the fourth is a cortical admixture phenotype (15). The tumors containing MAML3 C-terminal fusions were associated with a distinctive expression profile, active Wnt signaling pathway, low level of DNA methylation, and adverse clinical outcomes. The cortical admixture subtype is distinguished by the overexpression of several adrenal cortex markers. In addition, cortical admixture subtype contains germline mutations in MAX, supporting a distinctive underlying biology (15). Tumors with mutations in MYC-associated factor X (MAX) that regulates the MYC transcription factor are customarily assigned to cluster 2. However, MAX-associated tumors have a tendency for preferential secretion of normetanephrine compared with metanephrine (42, 43). Also, investigators have noted that the expression level of PNMT enzyme that converts norepinephrine to epinephrine is intermediate between tumors with the adrenergic phenotype and those with the noradrenergic phenotype (42). Hence, it appears that the MAX-associated tumors fall somewhere in between the cluster 1 and cluster 2 gene expression patterns. Krebs Cycle Mutations SDH and succinate The discovery of loss-of-function mutations in the TCA cycle enzymes SDH and fumarate hydratase (FH) in several cancers lends strong support to the proto-oncogenic function for metabolic products. Germline mutations in the SDHD gene were the first mitochondrial enzyme mutations documented in cancer (5). SDH is one of the key enzymes in the TCA cycle. SDH is composed of four different subunits: SDHA, SDHB, SDHC, and SDHD. Two additional proteins, SDHAF1 and SDHAF2, are required for its assembly. SDH converts succinate into fumarate and its function is required for proper operation of the mitochondrial respiratory chain (44). Mutations in SDH are found in renal carcinomas (45), T-cell leukemia (46), and gastrointestinal stromal tumors (47, 48). Most importantly, mutations in SDHB, SDHC, and SDHD subunits were identified in hereditary PCC and PGLs (5, 32, 33, 49–55; reviewed in 46). PCC/PGLs are rare, mostly benign, hereditary cancers of the chromaffin tissue that arise either in the adrenal medulla (PCC) or parasympathetic neuronal ganglia in the head and neck and sympathetic thoracolumbar tissue (PGL). Sympathetic PGLs produce catecholamines, whereas parasympathetic PGLs are most often nonsecretory. Mutations in SDHA and the SDH assembly factor SDHAF2 (required for flavination of SDH) are relatively more rare, but have been described in PCC/PGLs (30, 31, 57–59). In summary, mutations in every component of SDH have been identified and all of them are associated with PCC/PGLs. In contrast to IDH mutations (discussed later in this article), mutations in SDH genes obey the Knudson rule for tumor suppressors, with a loss-of-function germline mutation followed by a “second hit” somatic loss of the second allele in the tumor (60). Lack of SDH function in mouse cells leads to increase in pyruvate consumption and the action of pyruvate carboxylase is essential to replenish aspartate in SDH-deficient cells through pyruvate carboxylation. This metabolic reprogramming presents a vulnerability that could be explored to target tumors carrying SDHx mutation (61, 62). Inducible transcription factors [hypoxia-inducible factor (HIF)α/β dimers] are key gatekeepers of the response to low oxygen. It has been noted that tumors harboring SDH or FH mutations have a strong hypoxic signature (39, 40, 63). This observation prompted investigators to explore the interactions between Krebs cycle substrates and the activation of the hypoxic pathways. Unlike IDH-related tumors [e.g., acute myeloid leukemia (AML) or gliomas], PGL/PCCs have been historically closely associated with hypoxia, because these highly vascularized tumors arise either in tissues known to be susceptible to oxygen deprivation (i.e., cells of the adrenal medulla and organ of Zuckerkandl) or in cells known to serve as oxygen sensors (i.e., neurons of the carotid body). A higher incidence of carotid body tumors was reported for those who live at high altitudes (64–66). Hence, elucidation of hypoxic pathways can shed light on the genetic and metabolic alterations observed in these tumors and connection from metabolic alterations to tumorigenic process. Pseudohypoxia and HIFs are known to be involved in other hallmark cancer pathways that sustain tumor cell growth, vascularization, and proliferation (67, 68). Succinate accumulation resulting from SDH deficiency is the hallmark feature of SDH-deficient cells. Similar to 2HG oncometabolite, a product of the IDH gain-of-function mutations (discussed later in this article), succinate-mediated inhibition targets α-ketoglutarate (αKG)-dependent dioxygenases (Fig. 1). Although the role for pseudohypoxia and 2HG in the regulation of the prolyl-hydroxylases (PHDs) has been contested, succinate appears to be a viable candidate to serve as their inhibitor (69, 70). HIFα is continuously synthesized; however, under normoxic conditions, PHD-mediated hydroxylation marks it for degradation that involves the activity of the VHL ubiquitination complex (71). PHD-mediated hydroxylation requires oxygen as a cofactor, so the enzyme is inactive in hypoxia and becomes ineffective in hydroxylation of HIF1α that escapes VHL recognition. Thus, hypoxia protects HIFα from being degraded and the unmodified molecule translocates to the nucleus, where it forms a transcriptionally active HIF heterodimer with a stable HIF1β subunit. The low affinity of PHDs for oxygen makes them a reliable oxygen sensor (72). PHD inhibition by succinate leads to formation of an active HIF dimer even in the presence of abundant oxygen, a condition known as pseudohypoxia (69, 73). Figure 1. View largeDownload slide Biochemical pathways associated with metabolic enzyme mutations in PCC/PGL and other tumors. Loss-of-function mutations in genes encoding SDH subunits, FH, and MDH2 are shown as red stars. Gain-of-function mutations in IDH are shown in green. The mutations lead to the accumulation of the oncometabolites succinate, fumarate, and D-2HG. Oncometabolites interfere with normal function of αKG-dependent dioxygenases, such as PHDs and TET demethylases. The oncometabolite-stimulated pathways that lead to pseudohypoxia, DNA, and histone methylation are shown. MDH2, malate dehydrogenase; OAA, oxaloacetic acid; PHD, prolyl-hydroxylase; TET, ten-eleven translocation. Figure 1. View largeDownload slide Biochemical pathways associated with metabolic enzyme mutations in PCC/PGL and other tumors. Loss-of-function mutations in genes encoding SDH subunits, FH, and MDH2 are shown as red stars. Gain-of-function mutations in IDH are shown in green. The mutations lead to the accumulation of the oncometabolites succinate, fumarate, and D-2HG. Oncometabolites interfere with normal function of αKG-dependent dioxygenases, such as PHDs and TET demethylases. The oncometabolite-stimulated pathways that lead to pseudohypoxia, DNA, and histone methylation are shown. MDH2, malate dehydrogenase; OAA, oxaloacetic acid; PHD, prolyl-hydroxylase; TET, ten-eleven translocation. As a stable metabolite, mitochondrial succinate appears to be the most suitable signaling molecule to communicate its own excess to cytoplasmic proteins. However, other molecules can contribute to this communication. Reactive oxygen species arise as a result of TCA cycle and respiratory chain dysfunction and can serve as transmitters of SDH loss and oxygen insufficiency to PHDs (73–77). Activation of HIF and the pseudohypoxia pathway appears to be particularly important in SDH-driven PGL/PCCs (15). Gene expression profiling of the tumors confirmed the presence of hypoxia-associated gene expression. Among the activated genes are those encoding proteins involved in angiogenesis, most importantly vascular endothelial growth factor, which correlates with the highly vascular phenotype of these tumors. It was demonstrated that HIF-induced angiogenesis could be targeted clinically by using the receptor tyrosine kinase inhibitor sunitinib to suppress the angiogenic pathway with moderate tumor regression, stability, and decreased catecholamine production upon treatment (78, 79). These clinical cases provided the foundation for clinical trials to evaluate the benefit of this treatment in different groups of patients who have a mutation in genes associated with the pseudohypoxia pathway (80). The epithelial-to-mesenchymal transition–associated molecules such as LOXL2 or TWIST that are known to have key roles in vasculogenesis and metastasis are present in SDHx-driven cancer (81). The dedifferentiation in these tumors provides a rationale for the improved imaging modalities using 18F-2-fluoro-2-deoxy-d-glucose. It was proposed that the increased uptake in 18F-2-fluoro-2-deoxy-d-glucose observed in pseudohypoxic tumors is due to an elevated expression of glucose transporters and other glycolytic enzymes integral to glucose metabolism (82). Another reason for improved fluorodeoxyglucose detection in cluster 1 tumors is that HIF stabilization may directly increase glucose uptake and increased glycolysis even in the setting of normal oxygen conditions, as required by the Warburg effect. Newer, promising imaging modalities such as 68Ga DOTATE are being used that take advantage of somatostatin receptor expression in PCC/PGLs, and to identify the tumors that are prone to express these receptors (83). It has been reported that 18F- fluoro-l-dihydroxyphenylalanine tends to be a preferred imaging modality for differentiated head and neck PGLs because they are more likely to take up radiotracers for better tumor identification compared with tumors carrying SDHx mutations (9). In addition to SDH, genes encoding the other components of oxidative respiratory chain are dysregulated, contributing to the overall mitochondrial dysfunction (62). In summary, the pseudohypoxia pathway is an essential component of SDH-mediated tumorigenesis (15). IDH1, IDH2, and D-2HG Discovery of PCC/PGL–specific mutations in several genes associated with the Krebs cycle reinvigorated research in the metabolic makeup of tumor cells. These studies provided additional validation for Warburg’s insightful work. One of the metabolic mutations identified in the PCC/PGL tumors was a mutation in the cytosolic isocitrate dehydrogenase 1 (IDH1) gene (21). This finding was important because a whole-genome sequencing analysis performed just a year earlier identified recurrent mutations in the same IDH1 gene in glioma and AML cells (84, 85). The striking observation made by the authors was that IDH1 mutations in all cancers were largely confined to arginine R132 residing in the active site of the IDH1 protein. The mutant allele was always a missense and a wild-type IDH1 allele was retained in the tumor. Overall, this genotype did not appear to be a loss of function, but rather a dominant mutation. It was hypothesized that, in addition to losing the ability to catalyze the conversion between isocitrate and αKG, the R132 mutants are neomorphs that acquired a new function to convert αKG (also known as 2-oxoglutarate) to a chiral compound, d-2-hydroxyglutarate (D-2HG) (86) (Fig. 1). This later hypothesis quickly gained widespread acceptance. D-2HG is a rare metabolite normally only present in minute quantities; in human malignant gliomas carrying IDH1 mutations, however, markedly elevated levels of D-2HG were found (86). High levels of D-2HG produced by cancers containing IDH1 and IDH2 mutations could be used as a tractable biomarker—a finding that is immediately applicable clinically—for diagnoses, treatment, and follow-up of these tumors (87–90). These noninvasive methods would be advantageous over solid-tumor biopsy samples or procuring blood samples to obtain material for DNA sequencing. Metabolic screening for D-2HG also makes it possible to separate the truly neomorphic IDH mutations from polymorphic single nucleotide polymorphisms and sequencing artifacts that do not affect IDH enzyme activity. In summary, unlike changes in SDH subunits encoding genes that include truncations, insertions, and deletion mutations, IDH mutations are exclusively missense, dominant, oncogenic gain of function. From the very beginning, the ability of the mutant IDH to convert αKG into D-2HG led to the idea that enzymes relying on αKG for their activity could be affected. Several reports have provided evidence that 2HG can inhibit various αKG-dependent dioxygenase enzymes (91). Specifically, it has been proposed that 2HG is an inhibitor of PHD2, which targets HIF1α for degradation and that the increase in HIF1α level in IDH-null cells is the cancer culprit (92, 93). However, there is no clear hypoxic signature in IDH-driven tumors, and a link between D-2HG, PHD2 inhibition, and HIF1α stabilization was generally not supported (84, 94–98). Only the l isoform of 2HG appears to inhibit PHD activity (94, 98). Still, hypoxia should be considered one of the important factors that can increase the presence of oncometabolites (including D-2HG) and contribute to carcinogenesis. Although PHD-related/HIF stabilization mechanisms were proposed for all three oncometabolites discussed here—2HG, succinate, and fumarate (discussed later in this article)—it remains unclear whether D-2HG consistently uses these pathways in tumors (99). In contrast, in PCC/PGL tumors, mutations in SDHx completely overlap with the pseudohypoxic subtype (15). Given the close relationship among succinate, isocitrate, αKG, and 2HG, it is not surprising that there is commonality among the pathways affected by these molecules. The propensity of 2HG elevation to inhibit another family of αKG-dependent enzymes, the ten-eleven translocation (TET) family, was confirmed in several independent studies (92, 100, 101). TET proteins produce 5′-hydroxymethylcytosine, an intermediate in DNA demethylation reaction (Fig. 1). TET inhibition by 2HG is supported by the observation that the mutations in IDH1 or IDH2 were mutually exclusive with TET2 loss-of-function mutations in a large AML cohort (100, 101). Understanding the mechanism for biochemical fallout of the IDH mutations provides several opportunities for novel clinical approaches to IDH-driven tumors. The most straightforward strategy aims to inhibit the neomorphic activity of mutant IDH and its production of 2HG oncometabolite. Several inhibitors of IDH1 and -2 are in clinical trials (102–104). FH and fumarate Another TCA cycle enzyme, FH, converts fumarate into malate. Homozygous FH mutations are considered an inborn error of metabolism and lead to fumaric aciduria, with patients presenting with dysmorphia, infantile encephalopathy, and brain malformations (105). In contrast, loss of heterozygosity in patients carrying germline FH mutations causes hereditary leiomyomatosis and renal cell cancer (106, 107). FH is also downregulated in renal carcinomas (108), Leydig cell tumors (109), and, not dissimilar to IDH, deleted in neural tumors, neuroblastomas (110). Most importantly, FH mutations have been isolated in PCC/PGLs (16, 111), underscoring the propensity of the mutations in TCA-cycle enzymes to produce these tumors. Mutations in FH that result in clinical outcomes localize to conserved regions responsible for either the catalytic activity or the folding and stability of the enzyme, leading to abnormal accumulation of fumarate (112–115). Research into FH deficiency illustrates an important point: Loss-of function mutation does not simply create a backlog of the lone precursor (fumarate), it also leads to a comprehensive reorganization of the cell metabolism as a whole. For example, FH mutant cells use significantly more glutamine and upregulate genes required for heme synthesis and bilirubin excretion. Despite the defective TCA cycle, FH-deficient cells maintain adequate mitochondrial NADH production and membrane potential by compensatory increase in glucose consumption and lactate synthesis (113). Furthermore, the increase in unprocessed fumarate in FH-deficient cells forces the reversal of the urea cycle enzyme argininosuccinate lyase, driving the production of argininosuccinate from fumarate and arginine instead of aspartate and citrulline (114, 115). This makes FH-deficient cells auxotrophic for arginine, and depleting arginine from the medium reduces their proliferation and viability (115). Some oncogenes (e.g., RAS) produce tumors mostly when they are mutated; others (e.g., MYC) are rarely mutated and the mere overexpression (excess) of the wild-type protein is sufficient to drive oncogenic transformation. Similarly, although the definition of oncometabolite is most commonly applied to a normally absent 2HG, fumarate and succinate, the omnipresent components of the TCA cycle, cause a similar oncogenic effect when they accumulate in excess. Akin to 2HG and succinate, fumarate’s role in cancer is thought to include an epigenetic mechanism. In renal cancer (where the consequences of FH deficiency are best understood), fumarate inhibits histone and DNA (e.g., TETs) demethylases and affects the epigenetic landscape (116–118). It was also proposed that fumarate could inhibit other αKG-dependent dehydrogenases, specifically PHD, and induce pseudohypoxia acting through HIFs (67, 119). Malate dehydrogenase 2 Recently, Cascón et al. (120) described a patient who carried a mutation in yet another Krebs cycle enzyme, malate dehydrogenase 2 (MDH2). These tumors, deficient in the malate-oxidizing activity, accumulate fumarate. MDH2-mutated tumors have a global transcriptional profile similar to that of SDH-related tumors. All three metabolites—succinate, fumarate, and malate—can inhibit prolyl hydroxylation of HIFα (121, 122). A high fumarate-to-succinate ratio is common to the FH- and MDH2-mutated tumors, in contrast to SDHx-mutated tumors, and suggests that an alternative or additional mechanism can trigger oncogenesis in these patients. Conclusion Genetic analysis of affected patients and whole-genome approaches have substantially increased our understanding of PCC/PGL tumor biology. Although PCC/PGL tumors may have shown their many facets, like Dr. Jekyll and Mr. Hyde, commonalities that cause PCC/PGLs are now becoming apparent. Potential biomarkers such as 2HG, αKG, succinate, and IDH mutations are important candidates for identifying specific PCC/PGL phenotypes. The clinical and pharmacological applications of this research will continue to evolve, but it is already clear that genetic testing in all patients with PCC/PGL is required to identify the subtype of PCC/PGL and the patient’s at-risk family members. New research in metabolic pathophysiology in PCC/PGL has played an important role in understanding the function of these tumors. With further advancement in translational research, targeted treatments can be developed on the basis of the pathways these tumors are using for their growth and survival. Understanding other important components, such as distinctive epigenetic modifications in tumor genomes and their effect on the metabolism, will be key for developing personalized therapy in the near future. Abbreviations: Abbreviations: AML acute myeloid leukemia D-2HG d-2-hydroxyglutarate FH fumarate hydratase HIF hypoxia-inducible factor IDH isocitrate dehydrogenase IDH1 isocitrate dehydrogenase 1 MAX MYC-associated factor X MDH2 malate dehydrogenase 2 PCC pheochromocytoma PGL paraganglioma PHD prolyl-hydroxylase RET rearranged during transfection SDH succinate dehydrogenase SDHx succinate dehydrogenase subunits TCA tricarboxylic acid TET ten-eleven translocation VHL Von Hippel Lindau αKG αketoglutarate Acknowledgments Financial Support: This work was supported by the Gatorade Trust through funds distributed by the University of Florida, Department of Medicine, to H.K.G. Disclosure Summary: The authors have nothing to disclose. References 1. Neumann HP , Vortmeyer A , Schmidt D , Werner M , Erlic Z , Cascon A , Bausch B , Januszewicz A , Eng C . Evidence of MEN-2 in the original description of classic pheochromocytoma . N Engl J Med . 2007 ; 357 ( 13 ): 1311 – 1315 . Google Scholar CrossRef Search ADS PubMed 2. Pick L. Das Ganglioma embryonale sympathicum (Sympathoma embryonale), eine typische bösartige Geschwulstform des sympathischen Nervensystems . Berlin Klin Wochenschr . 1912 ; 49 : 16 – 22 . 3. Ghayee HK , Wyne KL , Yau FS , Snyder WH III , Holt S , Gokaslan ST , Nwariaku F . The many faces of pheochromocytoma . J Endocrinol Invest . 2008 ; 31 ( 5 ): 450 – 458 . Google Scholar CrossRef Search ADS PubMed 4. Otto AM . Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism . Cancer Metab . 2016 ; 4 ( 1 ): 5 . Google Scholar CrossRef Search ADS PubMed 5. Baysal BE , Ferrell RE , Willett-Brozick JE , Lawrence EC , Myssiorek D , Bosch A , van der Mey A , Taschner PE , Rubinstein WS , Myers EN , Richard CW III , Cornelisse CJ , Devilee P , Devlin B . Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma . Science . 2000 ; 287 ( 5454 ): 848 – 851 . Google Scholar CrossRef Search ADS PubMed 6. Lenders JW , Pacak K , Walther MM , Linehan WM , Mannelli M , Friberg P , Keiser HR , Goldstein DS , Eisenhofer G . Biochemical diagnosis of pheochromocytoma: which test is best ? JAMA . 2002 ; 287 ( 11 ): 1427 – 1434 . Google Scholar CrossRef Search ADS PubMed 7. Young WF Jr . Clinical practice. The incidentally discovered adrenal mass . N Engl J Med . 2007 ; 356 ( 6 ): 601 – 610 . Google Scholar CrossRef Search ADS PubMed 8. Timmers HJ , Chen CC , Carrasquillo JA , Whatley M , Ling A , Eisenhofer G , King KS , Rao JU , Wesley RA , Adams KT , Pacak K . Staging and functional characterization of pheochromocytoma and paraganglioma by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography . J Natl Cancer Inst . 2012 ; 104 ( 9 ): 700 – 708 . Google Scholar CrossRef Search ADS PubMed 9. Taïeb D , Pacak K . New insights into the nuclear imaging phenotypes of cluster 1 pheochromocytoma and paraganglioma . Trends Endocrinol Metab . 2017 ; 28 ( 11 ): 807 – 817 . Google Scholar CrossRef Search ADS PubMed 10. Favier J , Brière JJ , Burnichon N , Rivière J , Vescovo L , Benit P , Giscos-Douriez I , De Reyniès A , Bertherat J , Badoual C , Tissier F , Amar L , Libé R , Plouin PF , Jeunemaitre X , Rustin P , Gimenez-Roqueplo AP . The Warburg effect is genetically determined in inherited pheochromocytomas . PLoS One . 2009 ; 4 ( 9 ): e7094 . Google Scholar CrossRef Search ADS PubMed 11. Amar L , Baudin E , Burnichon N , Peyrard S , Silvera S , Bertherat J , Bertagna X , Schlumberger M , Jeunemaitre X , Gimenez-Roqueplo AP , Plouin PF . Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas . J Clin Endocrinol Metab . 2007 ; 92 ( 10 ): 3822 – 3828 . Google Scholar CrossRef Search ADS PubMed 12. Gupta G , Pacak K ; AACE Adrenal Scientific Committee . Precision medicine: an update on genotype-biochemical phenotype relationships in pheochromocytoma/paraganglioma patients . Endocr Pract . 2017 ; 23 ( 6 ): 690 – 704 . Google Scholar CrossRef Search ADS PubMed 13. Fishbein L , Khare S , Wubbenhorst B , DeSloover D , D’Andrea K , Merrill S , Cho NW , Greenberg RA , Else T , Montone K , LiVolsi V , Fraker D , Daber R , Cohen DL , Nathanson KL . Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas . Nat Commun . 2015 ; 6 ( 1 ): 6140 . Google Scholar CrossRef Search ADS PubMed 14. Comino-Méndez I , Tejera ÁM , Currás-Freixes M , Remacha L , Gonzalvo P , Tonda R , Letón R , Blasco MA , Robledo M , Cascón A . ATRX driver mutation in a composite malignant pheochromocytoma . Cancer Genet . 2016 ; 209 ( 6 ): 272 – 277 . Google Scholar CrossRef Search ADS PubMed 15. Fishbein L , Leshchiner I , Walter V , Danilova L , Robertson AG , Johnson AR , Lichtenberg TM , Murray BA , Ghayee HK , Else T , Ling S , Jefferys SR , de Cubas AA , Wenz B , Korpershoek E , Amelio AL , Makowski L , Rathmell WK , Gimenez-Roqueplo AP , Giordano TJ , Asa SL , Tischler AS , Pacak K , Nathanson KL , Wilkerson MD ; Cancer Genome Atlas Research Network . Comprehensive molecular characterization of pheochromocytoma and paraganglioma . Cancer Cell . 2017 ; 31 ( 2 ): 181 – 193 . Google Scholar CrossRef Search ADS PubMed 16. Castro-Vega LJ , Buffet A , De Cubas AA , Cascón A , Menara M , Khalifa E , Amar L , Azriel S , Bourdeau I , Chabre O , Currás-Freixes M , Franco-Vidal V , Guillaud-Bataille M , Simian C , Morin A , Letón R , Gómez-Graña A , Pollard PJ , Rustin P , Robledo M , Favier J , Gimenez-Roqueplo AP . Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas . Hum Mol Genet . 2014 ; 23 ( 9 ): 2440 – 2446 . Google Scholar CrossRef Search ADS PubMed 17. Zhuang Z , Yang C , Lorenzo F , Merino M , Fojo T , Kebebew E , Popovic V , Stratakis CA , Prchal JT , Pacak K . Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia . N Engl J Med . 2012 ; 367 ( 10 ): 922 – 930 . Google Scholar CrossRef Search ADS PubMed 18. Favier J , Buffet A , Gimenez-Roqueplo AP . HIF2A mutations in paraganglioma with polycythemia . N Engl J Med . 2012 ; 367 ( 22 ): 2161 – 2162, author reply 2161–2162 . Google Scholar CrossRef Search ADS PubMed 19. Comino-Méndez I , de Cubas AA , Bernal C , Álvarez-Escolá C , Sánchez-Malo C , Ramírez-Tortosa CL , Pedrinaci S , Rapizzi E , Ercolino T , Bernini G , Bacca A , Letón R , Pita G , Alonso MR , Leandro-García LJ , Gómez-Graña A , Inglada-Pérez L , Mancikova V , Rodríguez-Antona C , Mannelli M , Robledo M , Cascón A . Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis . Hum Mol Genet . 2013 ; 22 ( 11 ): 2169 – 2176 . Google Scholar CrossRef Search ADS PubMed 20. Crona J , Delgado Verdugo A , Maharjan R , Stålberg P , Granberg D , Hellman P , Björklund P . Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing . J Clin Endocrinol Metab . 2013 ; 98 ( 7 ): E1266 – E1271 . Google Scholar CrossRef Search ADS PubMed 21. Gaal J , Burnichon N , Korpershoek E , Roncelin I , Bertherat J , Plouin PF , de Krijger RR , Gimenez-Roqueplo AP , Dinjens WN . Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas . J Clin Endocrinol Metab . 2010 ; 95 ( 3 ): 1274 – 1278 . Google Scholar CrossRef Search ADS PubMed 22. Evenepoel L , Healers R , Vroonen L , Aydin S , Hamoir M , Maiter D , Vikkula M , Persu A . KIF1B and NF1 are the most frequently mutated genes in paraganglioma and pheochromocytoma tumors . Endocr Relat Cancer . 2017 ; 24 ( 8 ): L57 – L61 . Google Scholar CrossRef Search ADS PubMed 23. Comino-Méndez I , Gracia-Aznárez FJ , Schiavi F , Landa I , Leandro-García LJ , Letón R , Honrado E , Ramos-Medina R , Caronia D , Pita G , Gómez-Graña A , de Cubas AA , Inglada-Pérez L , Maliszewska A , Taschin E , Bobisse S , Pica G , Loli P , Hernández-Lavado R , Díaz JA , Gómez-Morales M , González-Neira A , Roncador G , Rodríguez-Antona C , Benítez J , Mannelli M , Opocher G , Robledo M , Cascón A . Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma . Nat Genet . 2011 ; 43 ( 7 ): 663 – 667 . Google Scholar CrossRef Search ADS PubMed 24. Cascon A , Comino-Méndez I , Currás-Freixes M , de Cubas AA , Contreras L , Richter S , Peitzsch M , Mancikova V , Inglada-Peréz L , Pérez-Barrios A , Calatayud M , Azriel S , Villar-Vicente R , Aller J , Setién F , Moran S , Garcia JF , Río-Machín A , Letón R , Gómez-Graña Á , Apellániz-Ruiz M , Roncador G , Esteller M , Rodríguez-Antona C , Satrústegui J , Eisenhofer G , Urioste M , Robledo M . Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene . J Natl Cancer Inst . 2015 ; 107 ( 5 ):djv053. 25. Santoro M , Rosati R , Grieco M , Berlingieri MT , D’Amato GL , de Franciscis V , Fusco A . The ret proto-oncogene is consistently expressed in human pheochromocytomas and thyroid medullary carcinomas . Oncogene . 1990 ; 5 ( 10 ): 1595 – 1598 . Google Scholar PubMed 26. Mulligan LM , Kwok JB , Healey CS , Elsdon MJ , Eng C , Gardner E , Love DR , Mole SE , Moore JK , Papi L , Ponder MA , Telenius H , Tunnacliffe A , Ponder BAJ . Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A . Nature . 1993 ; 363 ( 6428 ): 458 – 460 . Google Scholar CrossRef Search ADS PubMed 27. Hope DG , Mulvihill JJ . Malignancy in neurofibromatosis . Adv Neurol . 1981 ; 29 : 33 – 56 . Google Scholar PubMed 28. Jacks T , Shih TS , Schmitt EM , Bronson RT , Bernards A , Weinberg RA , Tumour predisposition in mice heterozygous for a targeted mutation in Nf1 . Nat Genet . 1994 ; 7 ( 3 ): 353 – 361 . Google Scholar CrossRef Search ADS PubMed 29. Yang C , Zhuang Z , Fliedner SM , Shankavaram U , Sun MG , Bullova P , Zhu R , Elkahloun AG , Kourlas PJ , Merino M , Kebebew E , Pacak K . Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia . J Mol Med (Berl) . 2015 ; 93 ( 1 ): 93 – 104 . Google Scholar CrossRef Search ADS PubMed 30. Ladroue C , Carcenac R , Leporrier M , Gad S , Le Hello C , Galateau-Salle F , Feunteun J , Pouysségur J , Richard S , Gardie B . PHD2 mutation and congenital erythrocytosis with paraganglioma . N Engl J Med . 2008 ; 359 ( 25 ): 2685 – 2692 . Google Scholar CrossRef Search ADS PubMed 31. Burnichon N , Brière JJ , Libé R , Vescovo L , Rivière J , Tissier F , Jouanno E , Jeunemaitre X , Bénit P , Tzagoloff A , Rustin P , Bertherat J , Favier J , Gimenez-Roqueplo AP . SDHA is a tumor suppressor gene causing paraganglioma . Hum Mol Genet . 2010 ; 19 ( 15 ): 3011 – 3020 . Google Scholar CrossRef Search ADS PubMed 32. Bayley JP , Kunst HP , Cascon A , Sampietro ML , Gaal J , Korpershoek E , Hinojar-Gutierrez A , Timmers HJ , Hoefsloot LH , Hermsen MA , Suárez C , Hussain AK , Vriends AH , Hes FJ , Jansen JC , Tops CM , Corssmit EP , de Knijff P , Lenders JW , Cremers CW , Devilee P , Dinjens WN , de Krijger RR , Robledo M . SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma . Lancet Oncol . 2010 ; 11 ( 4 ): 366 – 372 . Google Scholar CrossRef Search ADS PubMed 33. Astuti D , Latif F , Dallol A , Dahia PL , Douglas F , George E , Sköldberg F , Husebye ES , Eng C , Maher ER . Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma . Am J Hum Genet . 2001 ; 69 ( 1 ): 49 – 54 . Google Scholar CrossRef Search ADS PubMed 34. Niemann S , Müller U . Mutations in SDHC cause autosomal dominant paraganglioma, type 3 . Nat Genet . 2000 ; 26 ( 3 ): 268 – 270 . Google Scholar CrossRef Search ADS PubMed 35. Qin Y , Yao L , King EE , Buddavarapu K , Lenci RE , Chocron ES , Lechleiter JD , Sass M , Aronin N , Schiavi F , Boaretto F , Opocher G , Toledo RA , Toledo SP , Stiles C , Aguiar RC , Dahia PL . Germline mutations in TMEM127 confer susceptibility to pheochromocytoma . Nat Genet . 2010 ; 42 ( 3 ): 229 – 233 . Google Scholar CrossRef Search ADS PubMed 36. Neumann HP , Eng C , Mulligan LM , Glavac D , Zäuner I , Ponder BA , Crossey PA , Maher ER , Brauch H . Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II . JAMA . 1995 ; 274 ( 14 ): 1149 – 1151 . Google Scholar CrossRef Search ADS PubMed 37. Eisenhofer G , Pacak K , Huynh TT , Qin N , Bratslavsky G , Linehan WM , Mannelli M , Friberg P , Grebe SK , Timmers HJ , Bornstein SR , Lenders JW . Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma . Endocr Relat Cancer . 2010 ; 18 ( 1 ): 97 – 111 . Google Scholar CrossRef Search ADS PubMed 38. Eisenhofer G , Huynh TT , Pacak K , Brouwers FM , Walther MM , Linehan WM , Munson PJ , Mannelli M , Goldstein DS , Elkahloun AG . Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome . Endocr Relat Cancer . 2004 ; 11 ( 4 ): 897 – 911 . Google Scholar CrossRef Search ADS PubMed 39. Letouzé E , Martinelli C , Loriot C , Burnichon N , Abermil N , Ottolenghi C , Janin M , Menara M , Nguyen AT , Benit P , Buffet A , Marcaillou C , Bertherat J , Amar L , Rustin P , De Reyniès A , Gimenez-Roqueplo AP , Favier J . SDH mutations establish a hypermethylator phenotype in paraganglioma . Cancer Cell . 2013 ; 23 ( 6 ): 739 – 752 . Google Scholar CrossRef Search ADS PubMed 40. Burnichon N , Vescovo L , Amar L , Libé R , de Reynies A , Venisse A , Jouanno E , Laurendeau I , Parfait B , Bertherat J , Plouin PF , Jeunemaitre X , Favier J , Gimenez-Roqueplo AP . Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma . Hum Mol Genet . 2011 ; 20 ( 20 ): 3974 – 3985 . Google Scholar CrossRef Search ADS PubMed 41. Dahia PL , Ross KN , Wright ME , Hayashida CY , Santagata S , Barontini M , Kung AL , Sanso G , Powers JF , Tischler AS , Hodin R , Heitritter S , Moore F , Dluhy R , Sosa JA , Ocal IT , Benn DE , Marsh DJ , Robinson BG , Schneider K , Garber J , Arum SM , Korbonits M , Grossman A , Pigny P , Toledo SP , Nosé V , Li C , Stiles CDA . A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas . PLoS Genet . 2005 ; 1 ( 1 ): 72 – 80 . Google Scholar CrossRef Search ADS PubMed 42. Burnichon N , Cascón A , Schiavi F , Morales NP , Comino-Méndez I , Abermil N , Inglada-Pérez L , de Cubas AA , Amar L , Barontini M , de Quirós SB , Bertherat J , Bignon YJ , Blok MJ , Bobisse S , Borrego S , Castellano M , Chanson P , Chiara MD , Corssmit EP , Giacchè M , de Krijger RR , Ercolino T , Girerd X , Gómez-García EB , Gómez-Graña A , Guilhem I , Hes FJ , Honrado E , Korpershoek E , Lenders JW , Letón R , Mensenkamp AR , Merlo A , Mori L , Murat A , Pierre P , Plouin PF , Prodanov T , Quesada-Charneco M , Qin N , Rapizzi E , Raymond V , Reisch N , Roncador G , Ruiz-Ferrer M , Schillo F , Stegmann AP , Suarez C , Taschin E , Timmers HJ , Tops CM , Urioste M , Beuschlein F , Pacak K , Mannelli M , Dahia PL , Opocher G , Eisenhofer G , Gimenez-Roqueplo AP , Robledo M . MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma . Clin Cancer Res . 2012 ; 18 ( 10 ): 2828 – 2837 . Google Scholar CrossRef Search ADS PubMed 43. Korpershoek E , Koffy D , Eussen BH , Oudijk L , Papathomas TG , van Nederveen FH , Belt EJ , Franssen GJ , Restuccia DF , Krol NM , van der Luijt RB , Feelders RA , Oldenburg RA , van Ijcken WF , de Klein A , de Herder WW , de Krijger RR , Dinjens WN . Complex MAX rearrangement in a family with malignant pheochromocytoma, renal oncocytoma, and erythrocytosis . J Clin Endocrinol Metab . 2016 ; 101 ( 2 ): 453 – 460 . Google Scholar CrossRef Search ADS PubMed 44. Van Vranken JG , Na U , Winge DR , Rutter J . Protein-mediated assembly of succinate dehydrogenase and its cofactors . Crit Rev Biochem Mol Biol . 2015 ; 50 ( 2 ): 168 – 180 . Google Scholar CrossRef Search ADS PubMed 45. Vanharanta S , Buchta M , McWhinney SR , Virta SK , Peçzkowska M , Morrison CD , Lehtonen R , Januszewicz A , Järvinen H , Juhola M , Mecklin JP , Pukkala E , Herva R , Kiuru M , Nupponen NN , Aaltonen LA , Neumann HP , Eng C . Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma . Am J Hum Genet . 2004 ; 74 ( 1 ): 153 – 159 . Google Scholar CrossRef Search ADS PubMed 46. Baysal BE . A recurrent stop-codon mutation in succinate dehydrogenase subunit B gene in normal peripheral blood and childhood T-cell acute leukemia . PLoS One . 2007 ; 2 ( 5 ): e436 . Google Scholar CrossRef Search ADS PubMed 47. Stratakis CA , Carney JA . The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications . J Intern Med . 2009 ; 266 ( 1 ): 43 – 52 . Google Scholar CrossRef Search ADS PubMed 48. Janeway KA , Kim SY , Lodish M , Nosé V , Rustin P , Gaal J , Dahia PL , Liegl B , Ball ER , Raygada M , Lai AH , Kelly L , Hornick JL , O’Sullivan M , de Krijger RR , Dinjens WN , Demetri GD , Antonescu CR , Fletcher JA , Helman L , Stratakis CA ; NIH Pediatric and Wild-Type GIST Clinic . Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations . Proc Natl Acad Sci USA . 2011 ; 108 ( 1 ): 314 – 318 . Google Scholar CrossRef Search ADS PubMed 49. Müller U . Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC) . Neurogenetics . 2011 ; 12 ( 3 ): 175 – 181 . Google Scholar CrossRef Search ADS PubMed 50. Neumann HP , Pawlu C , Peczkowska M , Bausch B , McWhinney SR , Muresan M , Buchta M , Franke G , Klisch J , Bley TA , Hoegerle S , Boedeker CC , Opocher G , Schipper J , Januszewicz A , Eng C ; European-American Paraganglioma Study Group . Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations . JAMA . 2004 ; 292 ( 8 ): 943 – 951 . Google Scholar CrossRef Search ADS PubMed 51. Bardella C , Pollard PJ , Tomlinson I . SDH mutations in cancer . Biochim Biophys Acta . 2011 ; 1807 ( 11 ): 1432 – 1443 . Google Scholar CrossRef Search ADS PubMed 52. Bayley JP , van Minderhout I , Weiss MM , Jansen JC , Oomen PH , Menko FH , Pasini B , Ferrando B , Wong N , Alpert LC , Williams R , Blair E , Devilee P , Taschner PE . Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma . BMC Med Genet . 2006 ; 7 : 1 . Google Scholar CrossRef Search ADS PubMed 53. Benn DE , Croxson MS , Tucker K , Bambach CP , Richardson AL , Delbridge L , Pullan PT , Hammond J , Marsh DJ , Robinson BG . Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas . Oncogene . 2003 ; 22 ( 9 ): 1358 – 1364 . Google Scholar CrossRef Search ADS PubMed 54. Gimenez-Roqueplo AP , Favier J , Rustin P , Mourad JJ , Plouin PF , Corvol P , Rötig A , Jeunemaitre X . The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway . Am J Hum Genet . 2001 ; 69 ( 6 ): 1186 – 1197 . Google Scholar CrossRef Search ADS PubMed 55. Jochmanova I , Wolf KI , King KS , Nambuba J , Wesley R , Martucci V , Raygada M , Adams KT , Prodanov T , Fojo AT , Lazurova I , Pacak K . SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations . J Cancer Res Clin Oncol . 2017 ; 143 ( 8 ): 1421 – 1435 . Google Scholar CrossRef Search ADS PubMed 56. Wallace DC . Mitochondria and cancer . Nat Rev Cancer . 2012 ; 12 ( 10 ): 685 – 698 . Google Scholar CrossRef Search ADS PubMed 57. Hao HX , Khalimonchuk O , Schraders M , Dephoure N , Bayley JP , Kunst H , Devilee P , Cremers CW , Schiffman JD , Bentz BG , Gygi SP , Winge DR , Kremer H , Rutter J . SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma . Science . 2009 ; 325 ( 5944 ): 1139 – 1142 . Google Scholar CrossRef Search ADS PubMed 58. Italiano A , Chen CL , Sung YS , Singer S , DeMatteo RP , LaQuaglia MP , Besmer P , Socci N , Antonescu CR . SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors . BMC Cancer . 2012 ; 12 ( 1 ): 408 . Google Scholar CrossRef Search ADS PubMed 59. Bausch B , Schiavi F , Ni Y , Welander J , Patocs A , Ngeow J , Wellner U , Malinoc A , Taschin E , Barbon G , Lanza V , Söderkvist P , Stenman A , Larsson C , Svahn F , Chen JL , Marquard J , Fraenkel M , Walter MA , Peczkowska M , Prejbisz A , Jarzab B , Hasse-Lazar K , Petersenn S , Moeller LC , Meyer A , Reisch N , Trupka A , Brase C , Galiano M , Preuss SF , Kwok P , Lendvai N , Berisha G , Makay Ö , Boedeker CC , Weryha G , Racz K , Januszewicz A , Walz MK , Gimm O , Opocher G , Eng C , Neumann HPH ; European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group . Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention . JAMA Oncol . 2017 ; 3 ( 9 ): 1204 – 1212 . Google Scholar CrossRef Search ADS PubMed 60. Klein R , Lloyd R , Young W . Hereditary paraganglioma-pheochromocytoma syndromes . Seattle, WA : GeneReviews ; 2009 . https://www.ncbi.nlm.nih.gov/books/NBK1548/ 61. Cardaci S , Zheng L , MacKay G , van den Broek NJ , MacKenzie ED , Nixon C , Stevenson D , Tumanov S , Bulusu V , Kamphorst JJ , Vazquez A , Fleming S , Schiavi F , Kalna G , Blyth K , Strathdee D , Gottlieb E . Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis . Nat Cell Biol . 2015 ; 17 ( 10 ): 1317 – 1326 . Google Scholar CrossRef Search ADS PubMed 62. Lussey-Lepoutre C , Hollinshead KE , Ludwig C , Menara M , Morin A , Castro-Vega LJ , Parker SJ , Janin M , Martinelli C , Ottolenghi C , Metallo C , Gimenez-Roqueplo AP , Favier J , Tennant DA . Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism . Nat Commun . 2015 ; 6 ( 1 ): 8784 . Google Scholar CrossRef Search ADS PubMed 63. Brière JJ , Favier J , Bénit P , El Ghouzzi V , Lorenzato A , Rabier D , Di Renzo MF , Gimenez-Roqueplo AP , Rustin P . Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions . Hum Mol Genet . 2005 ; 14 ( 21 ): 3263 – 3269 . Google Scholar CrossRef Search ADS PubMed 64. Rodríguez-Cuevas S , López-Garza J , Labastida-Almendaro S . Carotid body tumors in inhabitants of altitudes higher than 2000 meters above sea level . Head Neck . 1998 ; 20 ( 5 ): 374 – 378 . Google Scholar CrossRef Search ADS PubMed 65. Astrom K , Cohen JE , Willett-Brozick JE , Aston CE , Baysal BE . Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect . Hum Genet . 2003 ; 113 ( 3 ): 228 – 237 . Google Scholar CrossRef Search ADS PubMed 66. Morin A , Letouzé E , Gimenez-Roqueplo AP , Favier J . Oncometabolites-driven tumorigenesis: from genetics to targeted therapy . Int J Cancer . 2014 ; 135 ( 10 ): 2237 – 2248 . Google Scholar CrossRef Search ADS PubMed 67. Pollard PJ , Brière JJ , Alam NA , Barwell J , Barclay E , Wortham NC , Hunt T , Mitchell M , Olpin S , Moat SJ , Hargreaves IP , Heales SJ , Chung YL , Griffiths JR , Dalgleish A , McGrath JA , Gleeson MJ , Hodgson SV , Poulsom R , Rustin P , Tomlinson IP . Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations . Hum Mol Genet . 2005 ; 14 ( 15 ): 2231 – 2239 . Google Scholar CrossRef Search ADS PubMed 68. Yang M , Pollard PJ . Succinate: a new epigenetic hacker . Cancer Cell . 2013 ; 23 ( 6 ): 709 – 711 . Google Scholar CrossRef Search ADS PubMed 69. Selak MA , Armour SM , MacKenzie ED , Boulahbel H , Watson DG , Mansfield KD , Pan Y , Simon MC , Thompson CB , Gottlieb E . Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase . Cancer Cell . 2005 ; 7 ( 1 ): 77 – 85 . Google Scholar CrossRef Search ADS PubMed 70. Lee KH , Choi E , Chun YS , Kim MS , Park JW . Differential responses of two degradation domains of HIF-1alpha to hypoxia and iron deficiency . Biochimie . 2006 ; 88 ( 2 ): 163 – 169 . Google Scholar CrossRef Search ADS PubMed 71. Kim WY , Kaelin WG . Role of VHL gene mutation in human cancer . J Clin Oncol . 2004 ; 22 ( 24 ): 4991 – 5004 . Google Scholar CrossRef Search ADS PubMed 72. Schofield CJ , Ratcliffe PJ . Oxygen sensing by HIF hydroxylases . Nat Rev Mol Cell Biol . 2004 ; 5 ( 5 ): 343 – 354 . Google Scholar CrossRef Search ADS PubMed 73. Gottlieb E , Tomlinson IP . Mitochondrial tumour suppressors: a genetic and biochemical update . Nat Rev Cancer . 2005 ; 5 ( 11 ): 857 – 866 . Google Scholar CrossRef Search ADS PubMed 74. Chandel NS , McClintock DS , Feliciano CE , Wood TM , Melendez JA , Rodriguez AM , Schumacker PT . Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing . J Biol Chem . 2000 ; 275 ( 33 ): 25130 – 25138 . Google Scholar CrossRef Search ADS PubMed 75. Guzy RD , Sharma B , Bell E , Chandel NS , Schumacker PT . Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis . Mol Cell Biol . 2008 ; 28 ( 2 ): 718 – 731 . Google Scholar CrossRef Search ADS PubMed 76. Ishii T , Yasuda K , Akatsuka A , Hino O , Hartman PS , Ishii N . A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis . Cancer Res . 2005 ; 65 ( 1 ): 203 – 209 . Google Scholar PubMed 77. Bayley JP , Devilee P . Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree ? Curr Opin Genet Dev . 2010 ; 20 ( 3 ): 324 – 329 . Google Scholar CrossRef Search ADS PubMed 78. Joshua AM , Ezzat S , Asa SL , Evans A , Broom R , Freeman M , Knox JJ . Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma . J Clin Endocrinol Metab . 2009 ; 94 ( 1 ): 5 – 9 . Google Scholar CrossRef Search ADS PubMed 79. Jimenez C , Cabanillas ME , Santarpia L , Jonasch E , Kyle KL , Lano EA , Matin SF , Nunez RF , Perrier ND , Phan A , Rich TA , Shah B , Williams MD , Waguespack SG . Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors . J Clin Endocrinol Metab . 2009 ; 94 ( 2 ): 386 – 391 . Google Scholar CrossRef Search ADS PubMed 80. ClinicalTrials.gov . Genetic analysis of pheochromocytomas, paragangliomas and associated conditions. ClinicalTrials.gov identifier: NCT03160274. Registered 19 October 2005. Updated 19 May 2017 . https://clinicaltrials.gov/ct2/show/NCT03160274. 81. Loriot C , Burnichon N , Gadessaud N , Vescovo L , Amar L , Libé R , Bertherat J , Plouin PF , Jeunemaitre X , Gimenez-Roqueplo AP , Favier J . Epithelial to mesenchymal transition is activated in metastatic pheochromocytomas and paragangliomas caused by SDHB gene mutations . J Clin Endocrinol Metab . 2012 ; 97 ( 6 ): E954 – E962 . Google Scholar CrossRef Search ADS PubMed 82. van Berkel A , Rao JU , Kusters B , Demir T , Visser E , Mensenkamp AR , van der Laak JA , Oosterwijk E , Lenders JW , Sweep FC , Wevers RA , Hermus AR , Langenhuijsen JF , Kunst DP , Pacak K , Gotthardt M , Timmers HJ . Correlation between in vivo 18F-FDG PET and immunohistochemical markers of glucose uptake and metabolism in pheochromocytoma and paraganglioma . J Nucl Med . 2014 ; 55 ( 8 ): 1253 – 1259 . Google Scholar CrossRef Search ADS PubMed 83. Chang CA , Pattison DA , Tothill RW , Kong G , Akhurst TJ , Hicks RJ , Hofman MS . (68)Ga-DOTATATE and (18)F-FDG PET/CT in paraganglioma and pheochromocytoma: utility, patterns and heterogeneity . Cancer Imaging . 2016 ; 16 ( 1 ): 22 . Google Scholar CrossRef Search ADS PubMed 84. Mardis ER , Ding L , Dooling DJ , Larson DE , McLellan MD , Chen K , Koboldt DC , Fulton RS , Delehaunty KD , McGrath SD , Fulton LA , Locke DP , Magrini VJ , Abbott RM , Vickery TL , Reed JS , Robinson JS , Wylie T , Smith SM , Carmichael L , Eldred JM , Harris CC , Walker J , Peck JB , Du F , Dukes AF , Sanderson GE , Brummett AM , Clark E , McMichael JF , Meyer RJ , Schindler JK , Pohl CS , Wallis JW , Shi X , Lin L , Schmidt H , Tang Y , Haipek C , Wiechert ME , Ivy JV , Kalicki J , Elliott G , Ries RE , Payton JE , Westervelt P , Tomasson MH , Watson MA , Baty J , Heath S , Shannon WD , Nagarajan R , Link DC , Walter MJ , Graubert TA , DiPersio JF , Wilson RK , Ley TJ . Recurring mutations found by sequencing an acute myeloid leukemia genome . N Engl J Med . 2009 ; 361 ( 11 ): 1058 – 1066 . Google Scholar CrossRef Search ADS PubMed 85. Parsons DW , Jones S , Zhang X , Lin JC , Leary RJ , Angenendt P , Mankoo P , Carter H , Siu IM , Gallia GL , Olivi A , McLendon R , Rasheed BA , Keir S , Nikolskaya T , Nikolsky Y , Busam DA , Tekleab H , Diaz LA Jr , Hartigan J , Smith DR , Strausberg RL , Marie SK , Shinjo SM , Yan H , Riggins GJ , Bigner DD , Karchin R , Papadopoulos N , Parmigiani G , Vogelstein B , Velculescu VE , Kinzler KW . An integrated genomic analysis of human glioblastoma multiforme . Science . 2008 ; 321 ( 5897 ): 1807 – 1812 . Google Scholar CrossRef Search ADS PubMed 86. Dang L , White DW , Gross S , Bennett BD , Bittinger MA , Driggers EM , Fantin VR , Jang HG , Jin S , Keenan MC , Marks KM , Prins RM , Ward PS , Yen KE , Liau LM , Rabinowitz JD , Cantley LC , Thompson CB , Vander Heiden MG , Su SM . Cancer-associated IDH1 mutations produce 2-hydroxyglutarate . Nature . 2009 ; 462 ( 7274 ): 739 – 744 . Google Scholar CrossRef Search ADS PubMed 87. Andronesi OC , Kim GS , Gerstner E , Batchelor T , Tzika AA , Fantin VR , Vander Heiden MG , Sorensen AG . Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy . Sci Transl Med . 2012 ; 4 ( 116 ): 116ra4 . Google Scholar CrossRef Search ADS PubMed 88. Choi C , Ganji SK , DeBerardinis RJ , Hatanpaa KJ , Rakheja D , Kovacs Z , Yang XL , Mashimo T , Raisanen JM , Marin-Valencia I , Pascual JM , Madden CJ , Mickey BE , Malloy CR , Bachoo RM , Maher EA . 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas . Nat Med . 2012 ; 18 ( 4 ): 624 – 629 . Google Scholar CrossRef Search ADS PubMed 89. Gross S , Cairns RA , Minden MD , Driggers EM , Bittinger MA , Jang HG , Sasaki M , Jin S , Schenkein DP , Su SM , Dang L , Fantin VR , Mak TW . Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations . J Exp Med . 2010 ; 207 ( 2 ): 339 – 344 . Google Scholar CrossRef Search ADS PubMed 90. Pope WB , Prins RM , Albert Thomas M , Nagarajan R , Yen KE , Bittinger MA , Salamon N , Chou AP , Yong WH , Soto H , Wilson N , Driggers E , Jang HG , Su SM , Schenkein DP , Lai A , Cloughesy TF , Kornblum HI , Wu H , Fantin VR , Liau LM . Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy . J Neurooncol . 2012 ; 107 ( 1 ): 197 – 205 . Google Scholar CrossRef Search ADS PubMed 91. Lu C , Ward PS , Kapoor GS , Rohle D , Turcan S , Abdel-Wahab O , Edwards CR , Khanin R , Figueroa ME , Melnick A , Wellen KE , O’Rourke DM , Berger SL , Chan TA , Levine RL , Mellinghoff IK , Thompson CB . IDH mutation impairs histone demethylation and results in a block to cell differentiation . Nature . 2012 ; 483 ( 7390 ): 474 – 478 . Google Scholar CrossRef Search ADS PubMed 92. Xu W , Yang H , Liu Y , Yang Y , Wang P , Kim SH , Ito S , Yang C , Wang P , Xiao MT , Liu LX , Jiang WQ , Liu J , Zhang JY , Wang B , Frye S , Zhang Y , Xu YH , Lei QY , Guan KL , Zhao SM , Xiong Y . Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases . Cancer Cell . 2011 ; 19 ( 1 ): 17 – 30 . Google Scholar CrossRef Search ADS PubMed 93. Zhao S , Lin Y , Xu W , Jiang W , Zha Z , Wang P , Yu W , Li Z , Gong L , Peng Y , Ding J , Lei Q , Guan KL , Xiong Y . Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha . Science . 2009 ; 324 ( 5924 ): 261 – 265 . Google Scholar CrossRef Search ADS PubMed 94. Chowdhury R , Yeoh KK , Tian YM , Hillringhaus L , Bagg EA , Rose NR , Leung IK , Li XS , Woon EC , Yang M , McDonough MA , King ON , Clifton IJ , Klose RJ , Claridge TD , Ratcliffe PJ , Schofield CJ , Kawamura A . The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases . EMBO Rep . 2011 ; 12 ( 5 ): 463 – 469 . Google Scholar CrossRef Search ADS PubMed 95. Jin G , Reitman ZJ , Spasojevic I , Batinic-Haberle I , Yang J , Schmidt-Kittler O , Bigner DD , Yan H . 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations . PLoS One . 2011 ; 6 ( 2 ): e16812 . Google Scholar CrossRef Search ADS PubMed 96. Metellus P , Colin C , Taieb D , Guedj E , Nanni-Metellus I , de Paula AM , Colavolpe C , Fuentes S , Dufour H , Barrie M , Chinot O , Ouafik L , Figarella-Branger D . IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients . J Neurooncol . 2011 ; 105 ( 3 ): 591 – 600 . Google Scholar CrossRef Search ADS PubMed 97. Williams SC , Karajannis MA , Chiriboga L , Golfinos JG , von Deimling A , Zagzag D . R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1α upregulation in adult glioma . Acta Neuropathol . 2011 ; 121 ( 2 ): 279 – 281 . Google Scholar CrossRef Search ADS PubMed 98. Burr SP , Costa AS , Grice GL , Timms RT , Lobb IT , Freisinger P , Dodd RB , Dougan G , Lehner PJ , Frezza C , Nathan JA . Mitochondrial protein lipoylation and the 2-oxoglutarate dehydrogenase complex controls HIF1α stability in aerobic conditions . Cell Metab . 2016 ; 24 ( 5 ): 740 – 752 . Google Scholar CrossRef Search ADS PubMed 99. Lee G , Won HS , Lee YM , Choi JW , Oh TI , Jang JH , Choi DK , Lim BO , Kim YJ , Park JW , Puigserver P , Lim JH . Oxidative dimerization of PHD2 is responsible for its inactivation and contributes to metabolic reprogramming via HIF-1α activation . Sci Rep . 2016 ; 6 : 18928 . Google Scholar CrossRef Search ADS PubMed 100. Figueroa ME , Abdel-Wahab O , Lu C , Ward PS , Patel J , Shih A , Li Y , Bhagwat N , Vasanthakumar A , Fernandez HF , Tallman MS , Sun Z , Wolniak K , Peeters JK , Liu W , Choe SE , Fantin VR , Paietta E , Löwenberg B , Licht JD , Godley LA , Delwel R , Valk PJ , Thompson CB , Levine RL , Melnick A . Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation . Cancer Cell . 2010 ; 18 ( 6 ): 553 – 567 . Google Scholar CrossRef Search ADS PubMed 101. Turcan S , Rohle D , Goenka A , Walsh LA , Fang F , Yilmaz E , Campos C , Fabius AW , Lu C , Ward PS , Thompson CB , Kaufman A , Guryanova O , Levine R , Heguy A , Viale A , Morris LG , Huse JT , Mellinghoff IK , Chan TA . IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype . Nature . 2012 ; 483 ( 7390 ): 479 – 483 . Google Scholar CrossRef Search ADS PubMed 102. Birendra KC , DiNardo CD . Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120 . Clin Lymphoma Myeloma Leuk . 2016 ; 16 ( 8 ): 460 – 465 . Google Scholar CrossRef Search ADS PubMed 103. Kats LM , Vervoort SJ , Cole R , Rogers AJ , Gregory GP , Vidacs E , Li J , Nagaraja R , Yen KE , Johnstone RW . A pharmacogenomic approach validates AG-221 as an effective and on-target therapy in IDH2 mutant AML . Leukemia . 2017 ; 31 ( 6 ): 1466 – 1470 . Google Scholar CrossRef Search ADS PubMed 104. Stein EM . IDH2 inhibition in AML: finally progress ? Best Pract Res Clin Haematol . 2015 ; 28 ( 2-3 ): 112 – 115 . Google Scholar CrossRef Search ADS PubMed 105. Kerrigan JF , Aleck KA , Tarby TJ , Bird CR , Heidenreich RA . Fumaric aciduria: clinical and imaging features . Ann Neurol . 2000 ; 47 ( 5 ): 583 – 588 . Google Scholar CrossRef Search ADS PubMed 106. Tomlinson IP , Alam NA , Rowan AJ , Barclay E , Jaeger EE , Kelsell D , Leigh I , Gorman P , Lamlum H , Rahman S , Roylance RR , Olpin S , Bevan S , Barker K , Hearle N , Houlston RS , Kiuru M , Lehtonen R , Karhu A , Vilkki S , Laiho P , Eklund C , Vierimaa O , Aittomäki K , Hietala M , Sistonen P , Paetau A , Salovaara R , Herva R , Launonen V , Aaltonen LA ; Multiple Leiomyoma Consortium . Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer . Nat Genet . 2002 ; 30 ( 4 ): 406 – 410 . Google Scholar CrossRef Search ADS PubMed 107. Frezza C , Pollard PJ , Gottlieb E . Inborn and acquired metabolic defects in cancer . J Mol Med (Berl) . 2011 ; 89 ( 3 ): 213 – 220 . Google Scholar CrossRef Search ADS PubMed 108. Ha YS , Chihara Y , Yoon HY , Kim YJ , Kim TH , Woo SH , Yun SJ , Kim IY , Hirao Y , Kim WJ . Downregulation of fumarate hydratase is related to tumorigenesis in sporadic renal cell cancer . Urol Int . 2013 ; 90 ( 2 ): 233 – 239 . Google Scholar CrossRef Search ADS PubMed 109. Carvajal-Carmona LG , Alam NA , Pollard PJ , Jones AM , Barclay E , Wortham N , Pignatelli M , Freeman A , Pomplun S , Ellis I , Poulsom R , El-Bahrawy MA , Berney DM , Tomlinson IP . Adult Leydig cell tumors of the testis caused by germline fumarate hydratase mutations . J Clin Endocrinol Metab . 2006 ; 91 ( 8 ): 3071 – 3075 . Google Scholar CrossRef Search ADS PubMed 110. Fieuw A , Kumps C , Schramm A , Pattyn F , Menten B , Antonacci F , Sudmant P , Schulte JH , Van Roy N , Vergult S , Buckley PG , De Paepe A , Noguera R , Versteeg R , Stallings R , Eggert A , Vandesompele J , De Preter K , Speleman F . Identification of a novel recurrent 1q42.2-1qter deletion in high risk MYCN single copy 11q deleted neuroblastomas . Int J Cancer . 2012 ; 130 ( 11 ): 2599 – 2606 . Google Scholar CrossRef Search ADS PubMed 111. Clark GR , Sciacovelli M , Gaude E , Walsh DM , Kirby G , Simpson MA , Trembath RC , Berg JN , Woodward ER , Kinning E , Morrison PJ , Frezza C , Maher ER . Germline FH mutations presenting with pheochromocytoma . J Clin Endocrinol Metab . 2014 ; 99 ( 10 ): E2046 – E2050 . Google Scholar CrossRef Search ADS PubMed 112. Picaud S , Kavanagh KL , Yue WW , Lee WH , Muller-Knapp S , Gileadi O , Sacchettini J , Oppermann U . Structural basis of fumarate hydratase deficiency . J Inherit Metab Dis . 2011 ; 34 ( 3 ): 671 – 676 . Google Scholar CrossRef Search ADS PubMed 113. Frezza C , Zheng L , Folger O , Rajagopalan KN , MacKenzie ED , Jerby L , Micaroni M , Chaneton B , Adam J , Hedley A , Kalna G , Tomlinson IP , Pollard PJ , Watson DG , Deberardinis RJ , Shlomi T , Ruppin E , Gottlieb E . Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase . Nature . 2011 ; 477 ( 7363 ): 225 – 228 . Google Scholar CrossRef Search ADS PubMed 114. Adam J , Yang M , Bauerschmidt C , Kitagawa M , O’Flaherty L , Maheswaran P , Özkan G , Sahgal N , Baban D , Kato K , Saito K , Iino K , Igarashi K , Stratford M , Pugh C , Tennant DA , Ludwig C , Davies B , Ratcliffe PJ , El-Bahrawy M , Ashrafian H , Soga T , Pollard PJ . A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia . Cell Reports . 2013 ; 3 ( 5 ): 1440 – 1448 . Google Scholar CrossRef Search ADS PubMed 115. Zheng L , MacKenzie ED , Karim SA , Hedley A , Blyth K , Kalna G , Watson DG , Szlosarek P , Frezza C , Gottlieb E . Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells . Cancer Metab . 2013 ; 1 ( 1 ): 12 . Google Scholar CrossRef Search ADS PubMed 116. Xiao M , Yang H , Xu W , Ma S , Lin H , Zhu H , Liu L , Liu Y , Yang C , Xu Y , Zhao S , Ye D , Xiong Y , Guan KL . Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors . Genes Dev . 2012 ; 26 ( 12 ): 1326 – 1338 . Google Scholar CrossRef Search ADS PubMed 117. Laukka T , Mariani CJ , Ihantola T , Cao JZ , Hokkanen J , Kaelin WG Jr , Godley LA , Koivunen P . Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes . J Biol Chem . 2016 ; 291 ( 8 ): 4256 – 4265 . Google Scholar CrossRef Search ADS PubMed 118. Linehan WM , Spellman PT , Ricketts CJ , Creighton CJ , Fei SS , Davis C , Wheeler DA , Murray BA , Schmidt L , Vocke CD , Peto M , Al Mamun AA , Shinbrot E , Sethi A , Brooks S , Rathmell WK , Brooks AN , Hoadley KA , Robertson AG , Brooks D , Bowlby R , Sadeghi S , Shen H , Weisenberger DJ , Bootwalla M , Baylin SB , Laird PW , Cherniack AD , Saksena G , Haake S , Li J , Liang H , Lu Y , Mills GB , Akbani R , Leiserson MD , Raphael BJ , Anur P , Bottaro D , Albiges L , Barnabas N , Choueiri TK , Czerniak B , Godwin AK , Hakimi AA , Ho TH , Hsieh J , Ittmann M , Kim WY , Krishnan B , Merino MJ , Mills Shaw KR , Reuter VE , Reznik E , Shelley CS , Shuch B , Signoretti S , Srinivasan R , Tamboli P , Thomas G , Tickoo S , Burnett K , Crain D , Gardner J , Lau K , Mallery D , Morris S , Paulauskis JD , Penny RJ , Shelton C , Shelton WT , Sherman M , Thompson E , Yena P , Avedon MT , Bowen J , Gastier-Foster JM , Gerken M , Leraas KM , Lichtenberg TM , Ramirez NC , Santos T , Wise L , Zmuda E , Demchok JA , Felau I , Hutter CM , Sheth M , Sofia HJ , Tarnuzzer R , Wang Z , Yang L , Zenklusen JC , Zhang J , Ayala B , Baboud J , Chudamani S , Liu J , Lolla L , Naresh R , Pihl T , Sun Q , Wan Y , Wu Y , Ally A , Balasundaram M , Balu S , Beroukhim R , Bodenheimer T , Buhay C , Butterfield YS , Carlsen R , Carter SL , Chao H , Chuah E , Clarke A , Covington KR , Dahdouli M , Dewal N , Dhalla N , Doddapaneni HV , Drummond JA , Gabriel SB , Gibbs RA , Guin R , Hale W , Hawes A , Hayes DN , Holt RA , Hoyle AP , Jefferys SR , Jones SJ , Jones CD , Kalra D , Kovar C , Lewis L , Li J , Ma Y , Marra MA , Mayo M , Meng S , Meyerson M , Mieczkowski PA , Moore RA , Morton D , Mose LE , Mungall AJ , Muzny D , Parker JS , Perou CM , Roach J , Schein JE , Schumacher SE , Shi Y , Simons JV , Sipahimalani P , Skelly T , Soloway MG , Sougnez C , Tam A , Tan D , Thiessen N , Veluvolu U , Wang M , Wilkerson MD , Wong T , Wu J , Xi L , Zhou J , Bedford J , Chen F , Fu Y , Gerstein M , Haussler D , Kasaian K , Lai P , Ling S , Radenbaugh A , Van Den Berg D , Weinstein JN , Zhu J , Albert M , Alexopoulou I , Andersen JJ , Auman JT , Bartlett J , Bastacky S , Bergsten J , Blute ML , Boice L , Bollag RJ , Boyd J , Castle E , Chen YB , Cheville JC , Curley E , Davies B , DeVolk A , Dhir R , Dike L , Eckman J , Engel J , Harr J , Hrebinko R , Huang M , Huelsenbeck-Dill L , Iacocca M , Jacobs B , Lobis M , Maranchie JK , McMeekin S , Myers J , Nelson J , Parfitt J , Parwani A , Petrelli N , Rabeno B , Roy S , Salner AL , Slaton J , Stanton M , Thompson RH , Thorne L , Tucker K , Weinberger PM , Winemiller C , Zach LA , Zuna R ; Cancer Genome Atlas Research Network . Comprehensive molecular characterization of papillary renal-cell carcinoma . N Engl J Med . 2016 ; 374 ( 2 ): 135 – 145 . Google Scholar CrossRef Search ADS PubMed 119. Isaacs JS , Jung YJ , Mole DR , Lee S , Torres-Cabala C , Chung YL , Merino M , Trepel J , Zbar B , Toro J , Ratcliffe PJ , Linehan WM , Neckers L . HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability . Cancer Cell . 2005 ; 8 ( 2 ): 143 – 153 . Google Scholar CrossRef Search ADS PubMed 120. Cascón A , Comino-Méndez I , Currás-Freixes M , de Cubas AA , Contreras L , Richter S , Peitzsch M , Mancikova V , Inglada-Pérez L , Pérez-Barrios A , Calatayud M , Azriel S , Villar-Vicente R , Aller J , Setién F , Moran S , Garcia JF , Río-Machín A , Letón R , Gómez-Graña Á , Apellániz-Ruiz M , Roncador G , Esteller M , Rodríguez-Antona C , Satrústegui J , Eisenhofer G , Urioste M , Robledo M . Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene . J Natl Cancer Inst . 2015 ; 107 ( 5 ). 121. Pan Y , Mansfield KD , Bertozzi CC , Rudenko V , Chan DA , Giaccia AJ , Simon MC . Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro . Mol Cell Biol . 2007 ; 27 ( 3 ): 912 – 925 . Google Scholar CrossRef Search ADS PubMed 122. Philip B , Ito K , Moreno-Sánchez R , Ralph SJ . HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression . Carcinogenesis . 2013 ; 34 ( 8 ): 1699 – 1707 . Google Scholar CrossRef Search ADS PubMed http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Pheochromocytoma/Paraganglioma: A Poster Child for Cancer Metabolism

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Publisher
Oxford University Press
ISSN
0021-972X
eISSN
1945-7197
D.O.I.
10.1210/jc.2017-01991
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Abstract

Abstract Context Pheochromocytomas (PCCs) are tumors that are derived from the chromaffin cells of the adrenal medulla. Extra-adrenal PCCs called paragangliomas (PGLs) are derived from the sympathetic and parasympathetic chain ganglia. PCCs secrete catecholamines, which cause hypertension and have adverse cardiovascular consequences as a result of catecholamine excess. PGLs may or may not produce catecholamines depending on their genetic type and anatomical location. The most worrisome aspect of these tumors is their ability to become aggressive and metastasize; there are no known cures for metastasized PGLs. Methods Original articles and reviews indexed in PubMed were identified by querying with specific PCC/PGL- and Krebs cycle pathway–related terms. Additional references were selected through the in-depth analysis of the relevant publications. Results We primarily discuss Krebs cycle mutations that can be instrumental in helping investigators identify key biological pathways and molecules that may serve as biomarkers of or treatment targets for PCC/PGL. Conclusion The mainstay of treatment of patients with PCC/PGLs is surgical. However, the tide may be turning with the discovery of new genes associated with PCC/PGLs that may shed light on oncometabolites used by these tumors. In 1886, the year that Robert Louis Stevenson published his novel Strange Case of Dr. Jekyll and Mr. Hyde, the first case of pheochromocytoma (PCC) was documented in Germany and described an 18-year-old woman with hypertensive crisis due to bilateral adrenal tumors (1). A quarter century later, the German pathologist Ludwig Pick noted a color change after adding chromium salts to adrenal medullary tumors. He coined the term pheochromocytoma from the Greek “phaios” (dark), “chroma” (color), and “cytoma” (tumor) (2). Over the years, PCC and paraganglioma (PGL) tumors have revealed, like the main character in Stevenson’s novel, their “split personality” in presentation and behavior (3), as well as in different genetic origins. The clues as to what has been hiding behind the changes come from Dr. Otto Warburg’s insightful observation that tumorogenic cells use glucose at higher levels compared with normal cells (4). Warburg went on to propose that this difference in metabolism is the fundamental cause of cancer. A better understanding of glucose metabolism came through the discovery of the tricarboxylic acid (TCA) cycle, or Krebs cycle, by Warburg’s mentee, Dr. Hans Krebs. By 1937, the TCA cycle was thoroughly described and provided the foundation of our understanding of cell metabolism. However, the connection between deficient Krebs cycle and cancer only became uncovered in the 21st century, when mutations were found in the succinate dehydrogenase subunits (SDHx) complex in hereditary PCC/PGLs. This discovery became the first documented case that directly linked defective mitochondrial protein with cancer predisposition (5). PCC/PGL: Where Are We Now? The initial diagnosis of PCC/PGL is usually made by inspecting plasma metanephrines or 24-hour urine for catecholamines and metanephrines (6, 7). After the biochemical evaluation, imaging studies such as computed tomography scans or magnetic resonance imaging studies are routinely conducted. To evaluate the extent of possible metastatic disease, the metaiodobenzylguanidine scan, for which a radiolabeled compound is taken up by PCC/PGL cells, traditionally is used to determine the tumor location. However, studies have reported better sensitivity for the fluorodeoxyglucose positron emission tomography approach to identify aggressive PCC/PGL disease (8). Recent research is recognizing 68Ga-labeled somatostatin analogs (DOTATATE) as a promising modality in finding PCC/PGL disease (9). This advancement in PCC/PGL imaging has come about through understanding of the alteration in glucose metabolism in these tumors (10). The mainstay of PCC/PGL treatment is surgical, because there are no medical therapies for metastatic disease and it is estimated that a median overall survival rate for patients with specific mutations is about 3 years (11). Even when a primary tumor is removed, a pathologist is not able to tell if the tumor is malignant or benign. The determination of metastatic disease is made when the patient’s imaging results are consistent with metastatic disease. Clues to whether the patient may have metastatic disease have come with the understanding of new genes associated with malignant behavior, which is discussed later in this review. Gene Clusters in PCC/PGLs We now know that there are 21 genes associated with PCC/PGLs—more than any number of genes associated with any other endocrine tumor (12) (Table 1). A few years before the discovery of mutations in the SDHx complex, genes associated with PCC syndromes were isolated, such as neurofibromatosis type 1 and rearranged during transfection (RET) proto-oncogene, which is associated with multiple endocrine neoplasia 2 syndrome. How these different genes cause PCC/PGLs has been an area of intense investigation. Table 1. Genes With Known Mutations in the PCC/PGL Tumors Gene Name Known Mutation Reference ATRX Loss of function (13, 14) CSDE1 Loss of function (15) FH Loss of function (16) HIF2A Gain of function (17–19) HRAS Gain of function (20) IDH1 Gain of function (21) KIF1B Loss of function (22) MAML3 Gain of function (15) MAX Loss of function (23) MDH2 Loss of function (24) MEN2 (RET) Gain of function (25, 26) NF1 Loss of function (27, 28) PHD1 (EGLN2) Loss of function (29) PHD2 (EGLN1) Loss of function (30) SDHA Loss of function (31) SDHAF2 Loss of function (32) SDHB Loss of function (33) SDHC Loss of function (34) SDHD Loss of function (5) TMEM127 Loss of function (35) VHL Loss of function (36) Gene Name Known Mutation Reference ATRX Loss of function (13, 14) CSDE1 Loss of function (15) FH Loss of function (16) HIF2A Gain of function (17–19) HRAS Gain of function (20) IDH1 Gain of function (21) KIF1B Loss of function (22) MAML3 Gain of function (15) MAX Loss of function (23) MDH2 Loss of function (24) MEN2 (RET) Gain of function (25, 26) NF1 Loss of function (27, 28) PHD1 (EGLN2) Loss of function (29) PHD2 (EGLN1) Loss of function (30) SDHA Loss of function (31) SDHAF2 Loss of function (32) SDHB Loss of function (33) SDHC Loss of function (34) SDHD Loss of function (5) TMEM127 Loss of function (35) VHL Loss of function (36) View Large Table 1. Genes With Known Mutations in the PCC/PGL Tumors Gene Name Known Mutation Reference ATRX Loss of function (13, 14) CSDE1 Loss of function (15) FH Loss of function (16) HIF2A Gain of function (17–19) HRAS Gain of function (20) IDH1 Gain of function (21) KIF1B Loss of function (22) MAML3 Gain of function (15) MAX Loss of function (23) MDH2 Loss of function (24) MEN2 (RET) Gain of function (25, 26) NF1 Loss of function (27, 28) PHD1 (EGLN2) Loss of function (29) PHD2 (EGLN1) Loss of function (30) SDHA Loss of function (31) SDHAF2 Loss of function (32) SDHB Loss of function (33) SDHC Loss of function (34) SDHD Loss of function (5) TMEM127 Loss of function (35) VHL Loss of function (36) Gene Name Known Mutation Reference ATRX Loss of function (13, 14) CSDE1 Loss of function (15) FH Loss of function (16) HIF2A Gain of function (17–19) HRAS Gain of function (20) IDH1 Gain of function (21) KIF1B Loss of function (22) MAML3 Gain of function (15) MAX Loss of function (23) MDH2 Loss of function (24) MEN2 (RET) Gain of function (25, 26) NF1 Loss of function (27, 28) PHD1 (EGLN2) Loss of function (29) PHD2 (EGLN1) Loss of function (30) SDHA Loss of function (31) SDHAF2 Loss of function (32) SDHB Loss of function (33) SDHC Loss of function (34) SDHD Loss of function (5) TMEM127 Loss of function (35) VHL Loss of function (36) View Large Depending on the type of the mutation, PCC/PGLs have distinctive gene expression profiles that assemble (cluster) in two so-called cluster groups (37, 38). Mutations affecting Von Hippel Lindau (VHL) protein and subunits of the succinate dehydrogenase (SDH) complex or SDH accessory proteins (i.e., SDHA, SDHB, SDHC, SDHD, and SDHAF2) and, rarely, isocitrate dehydrogenase (IDH) mutations, are among the causes of PCC/PGLs that make up cluster 1 tumors that are noradrenergic (37, 38). Most of the tumors that comprise cluster 1 are PGLs (37, 38). Their noradrenergic nature likely stems from the hypermethylation of the phenylethanolamine N-methyltransferase (PNMT) gene and subsequent lack of norepinephrine to epinephrine conversion. The proposed molecular mechanism involves inhibition of 2-oxoglutarate–dependent histone demethylases (39). Neurofibromatosis type 1, transmembrane protein 127 and multiple endocrine neoplasma type 2 due to mutations of the RET gene are well-established causes of hereditary PCC/PGLs; these tumors constitute cluster 2 (40, 41). Interestingly, DNA from the four living relatives of the first PCC/PGL patient described in 1886 demonstrated the presence of a germ-line RET mutation (1). Recently, The Cancer Genome Atlas Program verified the genetic composition of cluster 1 and cluster 2 tumors (15). Most gene mutations giving rise to the noradrenergic cluster 1 phenotype are primarily associated with Krebs cycle enzyme mutations as well as the pseudohypoxia pathway. In contrast, mutations in cluster 2 genes are found in tumors with adrenergic phenotype. This comprehensive project also uncovered two additional gene expression clusters (15). The third cluster is associated with an expression of the Mastermind-like 3 (MAML3)–fusion genes and the fourth is a cortical admixture phenotype (15). The tumors containing MAML3 C-terminal fusions were associated with a distinctive expression profile, active Wnt signaling pathway, low level of DNA methylation, and adverse clinical outcomes. The cortical admixture subtype is distinguished by the overexpression of several adrenal cortex markers. In addition, cortical admixture subtype contains germline mutations in MAX, supporting a distinctive underlying biology (15). Tumors with mutations in MYC-associated factor X (MAX) that regulates the MYC transcription factor are customarily assigned to cluster 2. However, MAX-associated tumors have a tendency for preferential secretion of normetanephrine compared with metanephrine (42, 43). Also, investigators have noted that the expression level of PNMT enzyme that converts norepinephrine to epinephrine is intermediate between tumors with the adrenergic phenotype and those with the noradrenergic phenotype (42). Hence, it appears that the MAX-associated tumors fall somewhere in between the cluster 1 and cluster 2 gene expression patterns. Krebs Cycle Mutations SDH and succinate The discovery of loss-of-function mutations in the TCA cycle enzymes SDH and fumarate hydratase (FH) in several cancers lends strong support to the proto-oncogenic function for metabolic products. Germline mutations in the SDHD gene were the first mitochondrial enzyme mutations documented in cancer (5). SDH is one of the key enzymes in the TCA cycle. SDH is composed of four different subunits: SDHA, SDHB, SDHC, and SDHD. Two additional proteins, SDHAF1 and SDHAF2, are required for its assembly. SDH converts succinate into fumarate and its function is required for proper operation of the mitochondrial respiratory chain (44). Mutations in SDH are found in renal carcinomas (45), T-cell leukemia (46), and gastrointestinal stromal tumors (47, 48). Most importantly, mutations in SDHB, SDHC, and SDHD subunits were identified in hereditary PCC and PGLs (5, 32, 33, 49–55; reviewed in 46). PCC/PGLs are rare, mostly benign, hereditary cancers of the chromaffin tissue that arise either in the adrenal medulla (PCC) or parasympathetic neuronal ganglia in the head and neck and sympathetic thoracolumbar tissue (PGL). Sympathetic PGLs produce catecholamines, whereas parasympathetic PGLs are most often nonsecretory. Mutations in SDHA and the SDH assembly factor SDHAF2 (required for flavination of SDH) are relatively more rare, but have been described in PCC/PGLs (30, 31, 57–59). In summary, mutations in every component of SDH have been identified and all of them are associated with PCC/PGLs. In contrast to IDH mutations (discussed later in this article), mutations in SDH genes obey the Knudson rule for tumor suppressors, with a loss-of-function germline mutation followed by a “second hit” somatic loss of the second allele in the tumor (60). Lack of SDH function in mouse cells leads to increase in pyruvate consumption and the action of pyruvate carboxylase is essential to replenish aspartate in SDH-deficient cells through pyruvate carboxylation. This metabolic reprogramming presents a vulnerability that could be explored to target tumors carrying SDHx mutation (61, 62). Inducible transcription factors [hypoxia-inducible factor (HIF)α/β dimers] are key gatekeepers of the response to low oxygen. It has been noted that tumors harboring SDH or FH mutations have a strong hypoxic signature (39, 40, 63). This observation prompted investigators to explore the interactions between Krebs cycle substrates and the activation of the hypoxic pathways. Unlike IDH-related tumors [e.g., acute myeloid leukemia (AML) or gliomas], PGL/PCCs have been historically closely associated with hypoxia, because these highly vascularized tumors arise either in tissues known to be susceptible to oxygen deprivation (i.e., cells of the adrenal medulla and organ of Zuckerkandl) or in cells known to serve as oxygen sensors (i.e., neurons of the carotid body). A higher incidence of carotid body tumors was reported for those who live at high altitudes (64–66). Hence, elucidation of hypoxic pathways can shed light on the genetic and metabolic alterations observed in these tumors and connection from metabolic alterations to tumorigenic process. Pseudohypoxia and HIFs are known to be involved in other hallmark cancer pathways that sustain tumor cell growth, vascularization, and proliferation (67, 68). Succinate accumulation resulting from SDH deficiency is the hallmark feature of SDH-deficient cells. Similar to 2HG oncometabolite, a product of the IDH gain-of-function mutations (discussed later in this article), succinate-mediated inhibition targets α-ketoglutarate (αKG)-dependent dioxygenases (Fig. 1). Although the role for pseudohypoxia and 2HG in the regulation of the prolyl-hydroxylases (PHDs) has been contested, succinate appears to be a viable candidate to serve as their inhibitor (69, 70). HIFα is continuously synthesized; however, under normoxic conditions, PHD-mediated hydroxylation marks it for degradation that involves the activity of the VHL ubiquitination complex (71). PHD-mediated hydroxylation requires oxygen as a cofactor, so the enzyme is inactive in hypoxia and becomes ineffective in hydroxylation of HIF1α that escapes VHL recognition. Thus, hypoxia protects HIFα from being degraded and the unmodified molecule translocates to the nucleus, where it forms a transcriptionally active HIF heterodimer with a stable HIF1β subunit. The low affinity of PHDs for oxygen makes them a reliable oxygen sensor (72). PHD inhibition by succinate leads to formation of an active HIF dimer even in the presence of abundant oxygen, a condition known as pseudohypoxia (69, 73). Figure 1. View largeDownload slide Biochemical pathways associated with metabolic enzyme mutations in PCC/PGL and other tumors. Loss-of-function mutations in genes encoding SDH subunits, FH, and MDH2 are shown as red stars. Gain-of-function mutations in IDH are shown in green. The mutations lead to the accumulation of the oncometabolites succinate, fumarate, and D-2HG. Oncometabolites interfere with normal function of αKG-dependent dioxygenases, such as PHDs and TET demethylases. The oncometabolite-stimulated pathways that lead to pseudohypoxia, DNA, and histone methylation are shown. MDH2, malate dehydrogenase; OAA, oxaloacetic acid; PHD, prolyl-hydroxylase; TET, ten-eleven translocation. Figure 1. View largeDownload slide Biochemical pathways associated with metabolic enzyme mutations in PCC/PGL and other tumors. Loss-of-function mutations in genes encoding SDH subunits, FH, and MDH2 are shown as red stars. Gain-of-function mutations in IDH are shown in green. The mutations lead to the accumulation of the oncometabolites succinate, fumarate, and D-2HG. Oncometabolites interfere with normal function of αKG-dependent dioxygenases, such as PHDs and TET demethylases. The oncometabolite-stimulated pathways that lead to pseudohypoxia, DNA, and histone methylation are shown. MDH2, malate dehydrogenase; OAA, oxaloacetic acid; PHD, prolyl-hydroxylase; TET, ten-eleven translocation. As a stable metabolite, mitochondrial succinate appears to be the most suitable signaling molecule to communicate its own excess to cytoplasmic proteins. However, other molecules can contribute to this communication. Reactive oxygen species arise as a result of TCA cycle and respiratory chain dysfunction and can serve as transmitters of SDH loss and oxygen insufficiency to PHDs (73–77). Activation of HIF and the pseudohypoxia pathway appears to be particularly important in SDH-driven PGL/PCCs (15). Gene expression profiling of the tumors confirmed the presence of hypoxia-associated gene expression. Among the activated genes are those encoding proteins involved in angiogenesis, most importantly vascular endothelial growth factor, which correlates with the highly vascular phenotype of these tumors. It was demonstrated that HIF-induced angiogenesis could be targeted clinically by using the receptor tyrosine kinase inhibitor sunitinib to suppress the angiogenic pathway with moderate tumor regression, stability, and decreased catecholamine production upon treatment (78, 79). These clinical cases provided the foundation for clinical trials to evaluate the benefit of this treatment in different groups of patients who have a mutation in genes associated with the pseudohypoxia pathway (80). The epithelial-to-mesenchymal transition–associated molecules such as LOXL2 or TWIST that are known to have key roles in vasculogenesis and metastasis are present in SDHx-driven cancer (81). The dedifferentiation in these tumors provides a rationale for the improved imaging modalities using 18F-2-fluoro-2-deoxy-d-glucose. It was proposed that the increased uptake in 18F-2-fluoro-2-deoxy-d-glucose observed in pseudohypoxic tumors is due to an elevated expression of glucose transporters and other glycolytic enzymes integral to glucose metabolism (82). Another reason for improved fluorodeoxyglucose detection in cluster 1 tumors is that HIF stabilization may directly increase glucose uptake and increased glycolysis even in the setting of normal oxygen conditions, as required by the Warburg effect. Newer, promising imaging modalities such as 68Ga DOTATE are being used that take advantage of somatostatin receptor expression in PCC/PGLs, and to identify the tumors that are prone to express these receptors (83). It has been reported that 18F- fluoro-l-dihydroxyphenylalanine tends to be a preferred imaging modality for differentiated head and neck PGLs because they are more likely to take up radiotracers for better tumor identification compared with tumors carrying SDHx mutations (9). In addition to SDH, genes encoding the other components of oxidative respiratory chain are dysregulated, contributing to the overall mitochondrial dysfunction (62). In summary, the pseudohypoxia pathway is an essential component of SDH-mediated tumorigenesis (15). IDH1, IDH2, and D-2HG Discovery of PCC/PGL–specific mutations in several genes associated with the Krebs cycle reinvigorated research in the metabolic makeup of tumor cells. These studies provided additional validation for Warburg’s insightful work. One of the metabolic mutations identified in the PCC/PGL tumors was a mutation in the cytosolic isocitrate dehydrogenase 1 (IDH1) gene (21). This finding was important because a whole-genome sequencing analysis performed just a year earlier identified recurrent mutations in the same IDH1 gene in glioma and AML cells (84, 85). The striking observation made by the authors was that IDH1 mutations in all cancers were largely confined to arginine R132 residing in the active site of the IDH1 protein. The mutant allele was always a missense and a wild-type IDH1 allele was retained in the tumor. Overall, this genotype did not appear to be a loss of function, but rather a dominant mutation. It was hypothesized that, in addition to losing the ability to catalyze the conversion between isocitrate and αKG, the R132 mutants are neomorphs that acquired a new function to convert αKG (also known as 2-oxoglutarate) to a chiral compound, d-2-hydroxyglutarate (D-2HG) (86) (Fig. 1). This later hypothesis quickly gained widespread acceptance. D-2HG is a rare metabolite normally only present in minute quantities; in human malignant gliomas carrying IDH1 mutations, however, markedly elevated levels of D-2HG were found (86). High levels of D-2HG produced by cancers containing IDH1 and IDH2 mutations could be used as a tractable biomarker—a finding that is immediately applicable clinically—for diagnoses, treatment, and follow-up of these tumors (87–90). These noninvasive methods would be advantageous over solid-tumor biopsy samples or procuring blood samples to obtain material for DNA sequencing. Metabolic screening for D-2HG also makes it possible to separate the truly neomorphic IDH mutations from polymorphic single nucleotide polymorphisms and sequencing artifacts that do not affect IDH enzyme activity. In summary, unlike changes in SDH subunits encoding genes that include truncations, insertions, and deletion mutations, IDH mutations are exclusively missense, dominant, oncogenic gain of function. From the very beginning, the ability of the mutant IDH to convert αKG into D-2HG led to the idea that enzymes relying on αKG for their activity could be affected. Several reports have provided evidence that 2HG can inhibit various αKG-dependent dioxygenase enzymes (91). Specifically, it has been proposed that 2HG is an inhibitor of PHD2, which targets HIF1α for degradation and that the increase in HIF1α level in IDH-null cells is the cancer culprit (92, 93). However, there is no clear hypoxic signature in IDH-driven tumors, and a link between D-2HG, PHD2 inhibition, and HIF1α stabilization was generally not supported (84, 94–98). Only the l isoform of 2HG appears to inhibit PHD activity (94, 98). Still, hypoxia should be considered one of the important factors that can increase the presence of oncometabolites (including D-2HG) and contribute to carcinogenesis. Although PHD-related/HIF stabilization mechanisms were proposed for all three oncometabolites discussed here—2HG, succinate, and fumarate (discussed later in this article)—it remains unclear whether D-2HG consistently uses these pathways in tumors (99). In contrast, in PCC/PGL tumors, mutations in SDHx completely overlap with the pseudohypoxic subtype (15). Given the close relationship among succinate, isocitrate, αKG, and 2HG, it is not surprising that there is commonality among the pathways affected by these molecules. The propensity of 2HG elevation to inhibit another family of αKG-dependent enzymes, the ten-eleven translocation (TET) family, was confirmed in several independent studies (92, 100, 101). TET proteins produce 5′-hydroxymethylcytosine, an intermediate in DNA demethylation reaction (Fig. 1). TET inhibition by 2HG is supported by the observation that the mutations in IDH1 or IDH2 were mutually exclusive with TET2 loss-of-function mutations in a large AML cohort (100, 101). Understanding the mechanism for biochemical fallout of the IDH mutations provides several opportunities for novel clinical approaches to IDH-driven tumors. The most straightforward strategy aims to inhibit the neomorphic activity of mutant IDH and its production of 2HG oncometabolite. Several inhibitors of IDH1 and -2 are in clinical trials (102–104). FH and fumarate Another TCA cycle enzyme, FH, converts fumarate into malate. Homozygous FH mutations are considered an inborn error of metabolism and lead to fumaric aciduria, with patients presenting with dysmorphia, infantile encephalopathy, and brain malformations (105). In contrast, loss of heterozygosity in patients carrying germline FH mutations causes hereditary leiomyomatosis and renal cell cancer (106, 107). FH is also downregulated in renal carcinomas (108), Leydig cell tumors (109), and, not dissimilar to IDH, deleted in neural tumors, neuroblastomas (110). Most importantly, FH mutations have been isolated in PCC/PGLs (16, 111), underscoring the propensity of the mutations in TCA-cycle enzymes to produce these tumors. Mutations in FH that result in clinical outcomes localize to conserved regions responsible for either the catalytic activity or the folding and stability of the enzyme, leading to abnormal accumulation of fumarate (112–115). Research into FH deficiency illustrates an important point: Loss-of function mutation does not simply create a backlog of the lone precursor (fumarate), it also leads to a comprehensive reorganization of the cell metabolism as a whole. For example, FH mutant cells use significantly more glutamine and upregulate genes required for heme synthesis and bilirubin excretion. Despite the defective TCA cycle, FH-deficient cells maintain adequate mitochondrial NADH production and membrane potential by compensatory increase in glucose consumption and lactate synthesis (113). Furthermore, the increase in unprocessed fumarate in FH-deficient cells forces the reversal of the urea cycle enzyme argininosuccinate lyase, driving the production of argininosuccinate from fumarate and arginine instead of aspartate and citrulline (114, 115). This makes FH-deficient cells auxotrophic for arginine, and depleting arginine from the medium reduces their proliferation and viability (115). Some oncogenes (e.g., RAS) produce tumors mostly when they are mutated; others (e.g., MYC) are rarely mutated and the mere overexpression (excess) of the wild-type protein is sufficient to drive oncogenic transformation. Similarly, although the definition of oncometabolite is most commonly applied to a normally absent 2HG, fumarate and succinate, the omnipresent components of the TCA cycle, cause a similar oncogenic effect when they accumulate in excess. Akin to 2HG and succinate, fumarate’s role in cancer is thought to include an epigenetic mechanism. In renal cancer (where the consequences of FH deficiency are best understood), fumarate inhibits histone and DNA (e.g., TETs) demethylases and affects the epigenetic landscape (116–118). It was also proposed that fumarate could inhibit other αKG-dependent dehydrogenases, specifically PHD, and induce pseudohypoxia acting through HIFs (67, 119). Malate dehydrogenase 2 Recently, Cascón et al. (120) described a patient who carried a mutation in yet another Krebs cycle enzyme, malate dehydrogenase 2 (MDH2). These tumors, deficient in the malate-oxidizing activity, accumulate fumarate. MDH2-mutated tumors have a global transcriptional profile similar to that of SDH-related tumors. All three metabolites—succinate, fumarate, and malate—can inhibit prolyl hydroxylation of HIFα (121, 122). A high fumarate-to-succinate ratio is common to the FH- and MDH2-mutated tumors, in contrast to SDHx-mutated tumors, and suggests that an alternative or additional mechanism can trigger oncogenesis in these patients. Conclusion Genetic analysis of affected patients and whole-genome approaches have substantially increased our understanding of PCC/PGL tumor biology. Although PCC/PGL tumors may have shown their many facets, like Dr. Jekyll and Mr. Hyde, commonalities that cause PCC/PGLs are now becoming apparent. Potential biomarkers such as 2HG, αKG, succinate, and IDH mutations are important candidates for identifying specific PCC/PGL phenotypes. The clinical and pharmacological applications of this research will continue to evolve, but it is already clear that genetic testing in all patients with PCC/PGL is required to identify the subtype of PCC/PGL and the patient’s at-risk family members. New research in metabolic pathophysiology in PCC/PGL has played an important role in understanding the function of these tumors. With further advancement in translational research, targeted treatments can be developed on the basis of the pathways these tumors are using for their growth and survival. Understanding other important components, such as distinctive epigenetic modifications in tumor genomes and their effect on the metabolism, will be key for developing personalized therapy in the near future. Abbreviations: Abbreviations: AML acute myeloid leukemia D-2HG d-2-hydroxyglutarate FH fumarate hydratase HIF hypoxia-inducible factor IDH isocitrate dehydrogenase IDH1 isocitrate dehydrogenase 1 MAX MYC-associated factor X MDH2 malate dehydrogenase 2 PCC pheochromocytoma PGL paraganglioma PHD prolyl-hydroxylase RET rearranged during transfection SDH succinate dehydrogenase SDHx succinate dehydrogenase subunits TCA tricarboxylic acid TET ten-eleven translocation VHL Von Hippel Lindau αKG αketoglutarate Acknowledgments Financial Support: This work was supported by the Gatorade Trust through funds distributed by the University of Florida, Department of Medicine, to H.K.G. Disclosure Summary: The authors have nothing to disclose. References 1. Neumann HP , Vortmeyer A , Schmidt D , Werner M , Erlic Z , Cascon A , Bausch B , Januszewicz A , Eng C . Evidence of MEN-2 in the original description of classic pheochromocytoma . N Engl J Med . 2007 ; 357 ( 13 ): 1311 – 1315 . Google Scholar CrossRef Search ADS PubMed 2. Pick L. Das Ganglioma embryonale sympathicum (Sympathoma embryonale), eine typische bösartige Geschwulstform des sympathischen Nervensystems . Berlin Klin Wochenschr . 1912 ; 49 : 16 – 22 . 3. Ghayee HK , Wyne KL , Yau FS , Snyder WH III , Holt S , Gokaslan ST , Nwariaku F . The many faces of pheochromocytoma . J Endocrinol Invest . 2008 ; 31 ( 5 ): 450 – 458 . Google Scholar CrossRef Search ADS PubMed 4. Otto AM . Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism . Cancer Metab . 2016 ; 4 ( 1 ): 5 . Google Scholar CrossRef Search ADS PubMed 5. Baysal BE , Ferrell RE , Willett-Brozick JE , Lawrence EC , Myssiorek D , Bosch A , van der Mey A , Taschner PE , Rubinstein WS , Myers EN , Richard CW III , Cornelisse CJ , Devilee P , Devlin B . Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma . Science . 2000 ; 287 ( 5454 ): 848 – 851 . Google Scholar CrossRef Search ADS PubMed 6. Lenders JW , Pacak K , Walther MM , Linehan WM , Mannelli M , Friberg P , Keiser HR , Goldstein DS , Eisenhofer G . Biochemical diagnosis of pheochromocytoma: which test is best ? JAMA . 2002 ; 287 ( 11 ): 1427 – 1434 . Google Scholar CrossRef Search ADS PubMed 7. Young WF Jr . Clinical practice. The incidentally discovered adrenal mass . N Engl J Med . 2007 ; 356 ( 6 ): 601 – 610 . Google Scholar CrossRef Search ADS PubMed 8. Timmers HJ , Chen CC , Carrasquillo JA , Whatley M , Ling A , Eisenhofer G , King KS , Rao JU , Wesley RA , Adams KT , Pacak K . Staging and functional characterization of pheochromocytoma and paraganglioma by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography . J Natl Cancer Inst . 2012 ; 104 ( 9 ): 700 – 708 . Google Scholar CrossRef Search ADS PubMed 9. Taïeb D , Pacak K . New insights into the nuclear imaging phenotypes of cluster 1 pheochromocytoma and paraganglioma . Trends Endocrinol Metab . 2017 ; 28 ( 11 ): 807 – 817 . Google Scholar CrossRef Search ADS PubMed 10. Favier J , Brière JJ , Burnichon N , Rivière J , Vescovo L , Benit P , Giscos-Douriez I , De Reyniès A , Bertherat J , Badoual C , Tissier F , Amar L , Libé R , Plouin PF , Jeunemaitre X , Rustin P , Gimenez-Roqueplo AP . The Warburg effect is genetically determined in inherited pheochromocytomas . PLoS One . 2009 ; 4 ( 9 ): e7094 . Google Scholar CrossRef Search ADS PubMed 11. Amar L , Baudin E , Burnichon N , Peyrard S , Silvera S , Bertherat J , Bertagna X , Schlumberger M , Jeunemaitre X , Gimenez-Roqueplo AP , Plouin PF . Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas . J Clin Endocrinol Metab . 2007 ; 92 ( 10 ): 3822 – 3828 . Google Scholar CrossRef Search ADS PubMed 12. Gupta G , Pacak K ; AACE Adrenal Scientific Committee . Precision medicine: an update on genotype-biochemical phenotype relationships in pheochromocytoma/paraganglioma patients . Endocr Pract . 2017 ; 23 ( 6 ): 690 – 704 . Google Scholar CrossRef Search ADS PubMed 13. Fishbein L , Khare S , Wubbenhorst B , DeSloover D , D’Andrea K , Merrill S , Cho NW , Greenberg RA , Else T , Montone K , LiVolsi V , Fraker D , Daber R , Cohen DL , Nathanson KL . Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas . Nat Commun . 2015 ; 6 ( 1 ): 6140 . Google Scholar CrossRef Search ADS PubMed 14. Comino-Méndez I , Tejera ÁM , Currás-Freixes M , Remacha L , Gonzalvo P , Tonda R , Letón R , Blasco MA , Robledo M , Cascón A . ATRX driver mutation in a composite malignant pheochromocytoma . Cancer Genet . 2016 ; 209 ( 6 ): 272 – 277 . Google Scholar CrossRef Search ADS PubMed 15. Fishbein L , Leshchiner I , Walter V , Danilova L , Robertson AG , Johnson AR , Lichtenberg TM , Murray BA , Ghayee HK , Else T , Ling S , Jefferys SR , de Cubas AA , Wenz B , Korpershoek E , Amelio AL , Makowski L , Rathmell WK , Gimenez-Roqueplo AP , Giordano TJ , Asa SL , Tischler AS , Pacak K , Nathanson KL , Wilkerson MD ; Cancer Genome Atlas Research Network . Comprehensive molecular characterization of pheochromocytoma and paraganglioma . Cancer Cell . 2017 ; 31 ( 2 ): 181 – 193 . Google Scholar CrossRef Search ADS PubMed 16. Castro-Vega LJ , Buffet A , De Cubas AA , Cascón A , Menara M , Khalifa E , Amar L , Azriel S , Bourdeau I , Chabre O , Currás-Freixes M , Franco-Vidal V , Guillaud-Bataille M , Simian C , Morin A , Letón R , Gómez-Graña A , Pollard PJ , Rustin P , Robledo M , Favier J , Gimenez-Roqueplo AP . Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas . Hum Mol Genet . 2014 ; 23 ( 9 ): 2440 – 2446 . Google Scholar CrossRef Search ADS PubMed 17. Zhuang Z , Yang C , Lorenzo F , Merino M , Fojo T , Kebebew E , Popovic V , Stratakis CA , Prchal JT , Pacak K . Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia . N Engl J Med . 2012 ; 367 ( 10 ): 922 – 930 . Google Scholar CrossRef Search ADS PubMed 18. Favier J , Buffet A , Gimenez-Roqueplo AP . HIF2A mutations in paraganglioma with polycythemia . N Engl J Med . 2012 ; 367 ( 22 ): 2161 – 2162, author reply 2161–2162 . Google Scholar CrossRef Search ADS PubMed 19. Comino-Méndez I , de Cubas AA , Bernal C , Álvarez-Escolá C , Sánchez-Malo C , Ramírez-Tortosa CL , Pedrinaci S , Rapizzi E , Ercolino T , Bernini G , Bacca A , Letón R , Pita G , Alonso MR , Leandro-García LJ , Gómez-Graña A , Inglada-Pérez L , Mancikova V , Rodríguez-Antona C , Mannelli M , Robledo M , Cascón A . Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis . Hum Mol Genet . 2013 ; 22 ( 11 ): 2169 – 2176 . Google Scholar CrossRef Search ADS PubMed 20. Crona J , Delgado Verdugo A , Maharjan R , Stålberg P , Granberg D , Hellman P , Björklund P . Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing . J Clin Endocrinol Metab . 2013 ; 98 ( 7 ): E1266 – E1271 . Google Scholar CrossRef Search ADS PubMed 21. Gaal J , Burnichon N , Korpershoek E , Roncelin I , Bertherat J , Plouin PF , de Krijger RR , Gimenez-Roqueplo AP , Dinjens WN . Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas . J Clin Endocrinol Metab . 2010 ; 95 ( 3 ): 1274 – 1278 . Google Scholar CrossRef Search ADS PubMed 22. Evenepoel L , Healers R , Vroonen L , Aydin S , Hamoir M , Maiter D , Vikkula M , Persu A . KIF1B and NF1 are the most frequently mutated genes in paraganglioma and pheochromocytoma tumors . Endocr Relat Cancer . 2017 ; 24 ( 8 ): L57 – L61 . Google Scholar CrossRef Search ADS PubMed 23. Comino-Méndez I , Gracia-Aznárez FJ , Schiavi F , Landa I , Leandro-García LJ , Letón R , Honrado E , Ramos-Medina R , Caronia D , Pita G , Gómez-Graña A , de Cubas AA , Inglada-Pérez L , Maliszewska A , Taschin E , Bobisse S , Pica G , Loli P , Hernández-Lavado R , Díaz JA , Gómez-Morales M , González-Neira A , Roncador G , Rodríguez-Antona C , Benítez J , Mannelli M , Opocher G , Robledo M , Cascón A . Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma . Nat Genet . 2011 ; 43 ( 7 ): 663 – 667 . Google Scholar CrossRef Search ADS PubMed 24. Cascon A , Comino-Méndez I , Currás-Freixes M , de Cubas AA , Contreras L , Richter S , Peitzsch M , Mancikova V , Inglada-Peréz L , Pérez-Barrios A , Calatayud M , Azriel S , Villar-Vicente R , Aller J , Setién F , Moran S , Garcia JF , Río-Machín A , Letón R , Gómez-Graña Á , Apellániz-Ruiz M , Roncador G , Esteller M , Rodríguez-Antona C , Satrústegui J , Eisenhofer G , Urioste M , Robledo M . Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene . J Natl Cancer Inst . 2015 ; 107 ( 5 ):djv053. 25. Santoro M , Rosati R , Grieco M , Berlingieri MT , D’Amato GL , de Franciscis V , Fusco A . The ret proto-oncogene is consistently expressed in human pheochromocytomas and thyroid medullary carcinomas . Oncogene . 1990 ; 5 ( 10 ): 1595 – 1598 . Google Scholar PubMed 26. Mulligan LM , Kwok JB , Healey CS , Elsdon MJ , Eng C , Gardner E , Love DR , Mole SE , Moore JK , Papi L , Ponder MA , Telenius H , Tunnacliffe A , Ponder BAJ . Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A . Nature . 1993 ; 363 ( 6428 ): 458 – 460 . Google Scholar CrossRef Search ADS PubMed 27. Hope DG , Mulvihill JJ . Malignancy in neurofibromatosis . Adv Neurol . 1981 ; 29 : 33 – 56 . Google Scholar PubMed 28. Jacks T , Shih TS , Schmitt EM , Bronson RT , Bernards A , Weinberg RA , Tumour predisposition in mice heterozygous for a targeted mutation in Nf1 . Nat Genet . 1994 ; 7 ( 3 ): 353 – 361 . Google Scholar CrossRef Search ADS PubMed 29. Yang C , Zhuang Z , Fliedner SM , Shankavaram U , Sun MG , Bullova P , Zhu R , Elkahloun AG , Kourlas PJ , Merino M , Kebebew E , Pacak K . Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia . J Mol Med (Berl) . 2015 ; 93 ( 1 ): 93 – 104 . Google Scholar CrossRef Search ADS PubMed 30. Ladroue C , Carcenac R , Leporrier M , Gad S , Le Hello C , Galateau-Salle F , Feunteun J , Pouysségur J , Richard S , Gardie B . PHD2 mutation and congenital erythrocytosis with paraganglioma . N Engl J Med . 2008 ; 359 ( 25 ): 2685 – 2692 . Google Scholar CrossRef Search ADS PubMed 31. Burnichon N , Brière JJ , Libé R , Vescovo L , Rivière J , Tissier F , Jouanno E , Jeunemaitre X , Bénit P , Tzagoloff A , Rustin P , Bertherat J , Favier J , Gimenez-Roqueplo AP . SDHA is a tumor suppressor gene causing paraganglioma . Hum Mol Genet . 2010 ; 19 ( 15 ): 3011 – 3020 . Google Scholar CrossRef Search ADS PubMed 32. Bayley JP , Kunst HP , Cascon A , Sampietro ML , Gaal J , Korpershoek E , Hinojar-Gutierrez A , Timmers HJ , Hoefsloot LH , Hermsen MA , Suárez C , Hussain AK , Vriends AH , Hes FJ , Jansen JC , Tops CM , Corssmit EP , de Knijff P , Lenders JW , Cremers CW , Devilee P , Dinjens WN , de Krijger RR , Robledo M . SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma . Lancet Oncol . 2010 ; 11 ( 4 ): 366 – 372 . Google Scholar CrossRef Search ADS PubMed 33. Astuti D , Latif F , Dallol A , Dahia PL , Douglas F , George E , Sköldberg F , Husebye ES , Eng C , Maher ER . Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma . Am J Hum Genet . 2001 ; 69 ( 1 ): 49 – 54 . Google Scholar CrossRef Search ADS PubMed 34. Niemann S , Müller U . Mutations in SDHC cause autosomal dominant paraganglioma, type 3 . Nat Genet . 2000 ; 26 ( 3 ): 268 – 270 . Google Scholar CrossRef Search ADS PubMed 35. Qin Y , Yao L , King EE , Buddavarapu K , Lenci RE , Chocron ES , Lechleiter JD , Sass M , Aronin N , Schiavi F , Boaretto F , Opocher G , Toledo RA , Toledo SP , Stiles C , Aguiar RC , Dahia PL . Germline mutations in TMEM127 confer susceptibility to pheochromocytoma . Nat Genet . 2010 ; 42 ( 3 ): 229 – 233 . Google Scholar CrossRef Search ADS PubMed 36. Neumann HP , Eng C , Mulligan LM , Glavac D , Zäuner I , Ponder BA , Crossey PA , Maher ER , Brauch H . Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II . JAMA . 1995 ; 274 ( 14 ): 1149 – 1151 . Google Scholar CrossRef Search ADS PubMed 37. Eisenhofer G , Pacak K , Huynh TT , Qin N , Bratslavsky G , Linehan WM , Mannelli M , Friberg P , Grebe SK , Timmers HJ , Bornstein SR , Lenders JW . Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma . Endocr Relat Cancer . 2010 ; 18 ( 1 ): 97 – 111 . Google Scholar CrossRef Search ADS PubMed 38. Eisenhofer G , Huynh TT , Pacak K , Brouwers FM , Walther MM , Linehan WM , Munson PJ , Mannelli M , Goldstein DS , Elkahloun AG . Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome . Endocr Relat Cancer . 2004 ; 11 ( 4 ): 897 – 911 . Google Scholar CrossRef Search ADS PubMed 39. Letouzé E , Martinelli C , Loriot C , Burnichon N , Abermil N , Ottolenghi C , Janin M , Menara M , Nguyen AT , Benit P , Buffet A , Marcaillou C , Bertherat J , Amar L , Rustin P , De Reyniès A , Gimenez-Roqueplo AP , Favier J . SDH mutations establish a hypermethylator phenotype in paraganglioma . Cancer Cell . 2013 ; 23 ( 6 ): 739 – 752 . Google Scholar CrossRef Search ADS PubMed 40. Burnichon N , Vescovo L , Amar L , Libé R , de Reynies A , Venisse A , Jouanno E , Laurendeau I , Parfait B , Bertherat J , Plouin PF , Jeunemaitre X , Favier J , Gimenez-Roqueplo AP . Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma . Hum Mol Genet . 2011 ; 20 ( 20 ): 3974 – 3985 . Google Scholar CrossRef Search ADS PubMed 41. Dahia PL , Ross KN , Wright ME , Hayashida CY , Santagata S , Barontini M , Kung AL , Sanso G , Powers JF , Tischler AS , Hodin R , Heitritter S , Moore F , Dluhy R , Sosa JA , Ocal IT , Benn DE , Marsh DJ , Robinson BG , Schneider K , Garber J , Arum SM , Korbonits M , Grossman A , Pigny P , Toledo SP , Nosé V , Li C , Stiles CDA . A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas . PLoS Genet . 2005 ; 1 ( 1 ): 72 – 80 . Google Scholar CrossRef Search ADS PubMed 42. Burnichon N , Cascón A , Schiavi F , Morales NP , Comino-Méndez I , Abermil N , Inglada-Pérez L , de Cubas AA , Amar L , Barontini M , de Quirós SB , Bertherat J , Bignon YJ , Blok MJ , Bobisse S , Borrego S , Castellano M , Chanson P , Chiara MD , Corssmit EP , Giacchè M , de Krijger RR , Ercolino T , Girerd X , Gómez-García EB , Gómez-Graña A , Guilhem I , Hes FJ , Honrado E , Korpershoek E , Lenders JW , Letón R , Mensenkamp AR , Merlo A , Mori L , Murat A , Pierre P , Plouin PF , Prodanov T , Quesada-Charneco M , Qin N , Rapizzi E , Raymond V , Reisch N , Roncador G , Ruiz-Ferrer M , Schillo F , Stegmann AP , Suarez C , Taschin E , Timmers HJ , Tops CM , Urioste M , Beuschlein F , Pacak K , Mannelli M , Dahia PL , Opocher G , Eisenhofer G , Gimenez-Roqueplo AP , Robledo M . MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma . Clin Cancer Res . 2012 ; 18 ( 10 ): 2828 – 2837 . Google Scholar CrossRef Search ADS PubMed 43. Korpershoek E , Koffy D , Eussen BH , Oudijk L , Papathomas TG , van Nederveen FH , Belt EJ , Franssen GJ , Restuccia DF , Krol NM , van der Luijt RB , Feelders RA , Oldenburg RA , van Ijcken WF , de Klein A , de Herder WW , de Krijger RR , Dinjens WN . Complex MAX rearrangement in a family with malignant pheochromocytoma, renal oncocytoma, and erythrocytosis . J Clin Endocrinol Metab . 2016 ; 101 ( 2 ): 453 – 460 . Google Scholar CrossRef Search ADS PubMed 44. Van Vranken JG , Na U , Winge DR , Rutter J . Protein-mediated assembly of succinate dehydrogenase and its cofactors . Crit Rev Biochem Mol Biol . 2015 ; 50 ( 2 ): 168 – 180 . Google Scholar CrossRef Search ADS PubMed 45. Vanharanta S , Buchta M , McWhinney SR , Virta SK , Peçzkowska M , Morrison CD , Lehtonen R , Januszewicz A , Järvinen H , Juhola M , Mecklin JP , Pukkala E , Herva R , Kiuru M , Nupponen NN , Aaltonen LA , Neumann HP , Eng C . Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma . Am J Hum Genet . 2004 ; 74 ( 1 ): 153 – 159 . Google Scholar CrossRef Search ADS PubMed 46. Baysal BE . A recurrent stop-codon mutation in succinate dehydrogenase subunit B gene in normal peripheral blood and childhood T-cell acute leukemia . PLoS One . 2007 ; 2 ( 5 ): e436 . Google Scholar CrossRef Search ADS PubMed 47. Stratakis CA , Carney JA . The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications . J Intern Med . 2009 ; 266 ( 1 ): 43 – 52 . Google Scholar CrossRef Search ADS PubMed 48. Janeway KA , Kim SY , Lodish M , Nosé V , Rustin P , Gaal J , Dahia PL , Liegl B , Ball ER , Raygada M , Lai AH , Kelly L , Hornick JL , O’Sullivan M , de Krijger RR , Dinjens WN , Demetri GD , Antonescu CR , Fletcher JA , Helman L , Stratakis CA ; NIH Pediatric and Wild-Type GIST Clinic . Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations . Proc Natl Acad Sci USA . 2011 ; 108 ( 1 ): 314 – 318 . Google Scholar CrossRef Search ADS PubMed 49. Müller U . Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC) . Neurogenetics . 2011 ; 12 ( 3 ): 175 – 181 . Google Scholar CrossRef Search ADS PubMed 50. Neumann HP , Pawlu C , Peczkowska M , Bausch B , McWhinney SR , Muresan M , Buchta M , Franke G , Klisch J , Bley TA , Hoegerle S , Boedeker CC , Opocher G , Schipper J , Januszewicz A , Eng C ; European-American Paraganglioma Study Group . Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations . JAMA . 2004 ; 292 ( 8 ): 943 – 951 . Google Scholar CrossRef Search ADS PubMed 51. Bardella C , Pollard PJ , Tomlinson I . SDH mutations in cancer . Biochim Biophys Acta . 2011 ; 1807 ( 11 ): 1432 – 1443 . Google Scholar CrossRef Search ADS PubMed 52. Bayley JP , van Minderhout I , Weiss MM , Jansen JC , Oomen PH , Menko FH , Pasini B , Ferrando B , Wong N , Alpert LC , Williams R , Blair E , Devilee P , Taschner PE . Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma . BMC Med Genet . 2006 ; 7 : 1 . Google Scholar CrossRef Search ADS PubMed 53. Benn DE , Croxson MS , Tucker K , Bambach CP , Richardson AL , Delbridge L , Pullan PT , Hammond J , Marsh DJ , Robinson BG . Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas . Oncogene . 2003 ; 22 ( 9 ): 1358 – 1364 . Google Scholar CrossRef Search ADS PubMed 54. Gimenez-Roqueplo AP , Favier J , Rustin P , Mourad JJ , Plouin PF , Corvol P , Rötig A , Jeunemaitre X . The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway . Am J Hum Genet . 2001 ; 69 ( 6 ): 1186 – 1197 . Google Scholar CrossRef Search ADS PubMed 55. Jochmanova I , Wolf KI , King KS , Nambuba J , Wesley R , Martucci V , Raygada M , Adams KT , Prodanov T , Fojo AT , Lazurova I , Pacak K . SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations . J Cancer Res Clin Oncol . 2017 ; 143 ( 8 ): 1421 – 1435 . Google Scholar CrossRef Search ADS PubMed 56. Wallace DC . Mitochondria and cancer . Nat Rev Cancer . 2012 ; 12 ( 10 ): 685 – 698 . Google Scholar CrossRef Search ADS PubMed 57. Hao HX , Khalimonchuk O , Schraders M , Dephoure N , Bayley JP , Kunst H , Devilee P , Cremers CW , Schiffman JD , Bentz BG , Gygi SP , Winge DR , Kremer H , Rutter J . SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma . Science . 2009 ; 325 ( 5944 ): 1139 – 1142 . Google Scholar CrossRef Search ADS PubMed 58. Italiano A , Chen CL , Sung YS , Singer S , DeMatteo RP , LaQuaglia MP , Besmer P , Socci N , Antonescu CR . SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors . BMC Cancer . 2012 ; 12 ( 1 ): 408 . Google Scholar CrossRef Search ADS PubMed 59. Bausch B , Schiavi F , Ni Y , Welander J , Patocs A , Ngeow J , Wellner U , Malinoc A , Taschin E , Barbon G , Lanza V , Söderkvist P , Stenman A , Larsson C , Svahn F , Chen JL , Marquard J , Fraenkel M , Walter MA , Peczkowska M , Prejbisz A , Jarzab B , Hasse-Lazar K , Petersenn S , Moeller LC , Meyer A , Reisch N , Trupka A , Brase C , Galiano M , Preuss SF , Kwok P , Lendvai N , Berisha G , Makay Ö , Boedeker CC , Weryha G , Racz K , Januszewicz A , Walz MK , Gimm O , Opocher G , Eng C , Neumann HPH ; European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group . Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention . JAMA Oncol . 2017 ; 3 ( 9 ): 1204 – 1212 . Google Scholar CrossRef Search ADS PubMed 60. Klein R , Lloyd R , Young W . Hereditary paraganglioma-pheochromocytoma syndromes . Seattle, WA : GeneReviews ; 2009 . https://www.ncbi.nlm.nih.gov/books/NBK1548/ 61. Cardaci S , Zheng L , MacKay G , van den Broek NJ , MacKenzie ED , Nixon C , Stevenson D , Tumanov S , Bulusu V , Kamphorst JJ , Vazquez A , Fleming S , Schiavi F , Kalna G , Blyth K , Strathdee D , Gottlieb E . Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis . Nat Cell Biol . 2015 ; 17 ( 10 ): 1317 – 1326 . Google Scholar CrossRef Search ADS PubMed 62. Lussey-Lepoutre C , Hollinshead KE , Ludwig C , Menara M , Morin A , Castro-Vega LJ , Parker SJ , Janin M , Martinelli C , Ottolenghi C , Metallo C , Gimenez-Roqueplo AP , Favier J , Tennant DA . Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism . Nat Commun . 2015 ; 6 ( 1 ): 8784 . Google Scholar CrossRef Search ADS PubMed 63. Brière JJ , Favier J , Bénit P , El Ghouzzi V , Lorenzato A , Rabier D , Di Renzo MF , Gimenez-Roqueplo AP , Rustin P . Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions . Hum Mol Genet . 2005 ; 14 ( 21 ): 3263 – 3269 . Google Scholar CrossRef Search ADS PubMed 64. Rodríguez-Cuevas S , López-Garza J , Labastida-Almendaro S . Carotid body tumors in inhabitants of altitudes higher than 2000 meters above sea level . Head Neck . 1998 ; 20 ( 5 ): 374 – 378 . Google Scholar CrossRef Search ADS PubMed 65. Astrom K , Cohen JE , Willett-Brozick JE , Aston CE , Baysal BE . Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect . Hum Genet . 2003 ; 113 ( 3 ): 228 – 237 . Google Scholar CrossRef Search ADS PubMed 66. Morin A , Letouzé E , Gimenez-Roqueplo AP , Favier J . Oncometabolites-driven tumorigenesis: from genetics to targeted therapy . Int J Cancer . 2014 ; 135 ( 10 ): 2237 – 2248 . Google Scholar CrossRef Search ADS PubMed 67. Pollard PJ , Brière JJ , Alam NA , Barwell J , Barclay E , Wortham NC , Hunt T , Mitchell M , Olpin S , Moat SJ , Hargreaves IP , Heales SJ , Chung YL , Griffiths JR , Dalgleish A , McGrath JA , Gleeson MJ , Hodgson SV , Poulsom R , Rustin P , Tomlinson IP . Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations . Hum Mol Genet . 2005 ; 14 ( 15 ): 2231 – 2239 . Google Scholar CrossRef Search ADS PubMed 68. Yang M , Pollard PJ . Succinate: a new epigenetic hacker . Cancer Cell . 2013 ; 23 ( 6 ): 709 – 711 . Google Scholar CrossRef Search ADS PubMed 69. Selak MA , Armour SM , MacKenzie ED , Boulahbel H , Watson DG , Mansfield KD , Pan Y , Simon MC , Thompson CB , Gottlieb E . Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase . Cancer Cell . 2005 ; 7 ( 1 ): 77 – 85 . Google Scholar CrossRef Search ADS PubMed 70. Lee KH , Choi E , Chun YS , Kim MS , Park JW . Differential responses of two degradation domains of HIF-1alpha to hypoxia and iron deficiency . Biochimie . 2006 ; 88 ( 2 ): 163 – 169 . Google Scholar CrossRef Search ADS PubMed 71. Kim WY , Kaelin WG . Role of VHL gene mutation in human cancer . J Clin Oncol . 2004 ; 22 ( 24 ): 4991 – 5004 . Google Scholar CrossRef Search ADS PubMed 72. Schofield CJ , Ratcliffe PJ . Oxygen sensing by HIF hydroxylases . Nat Rev Mol Cell Biol . 2004 ; 5 ( 5 ): 343 – 354 . Google Scholar CrossRef Search ADS PubMed 73. Gottlieb E , Tomlinson IP . Mitochondrial tumour suppressors: a genetic and biochemical update . Nat Rev Cancer . 2005 ; 5 ( 11 ): 857 – 866 . Google Scholar CrossRef Search ADS PubMed 74. Chandel NS , McClintock DS , Feliciano CE , Wood TM , Melendez JA , Rodriguez AM , Schumacker PT . Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing . J Biol Chem . 2000 ; 275 ( 33 ): 25130 – 25138 . Google Scholar CrossRef Search ADS PubMed 75. Guzy RD , Sharma B , Bell E , Chandel NS , Schumacker PT . Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis . Mol Cell Biol . 2008 ; 28 ( 2 ): 718 – 731 . Google Scholar CrossRef Search ADS PubMed 76. Ishii T , Yasuda K , Akatsuka A , Hino O , Hartman PS , Ishii N . A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis . Cancer Res . 2005 ; 65 ( 1 ): 203 – 209 . Google Scholar PubMed 77. Bayley JP , Devilee P . Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree ? Curr Opin Genet Dev . 2010 ; 20 ( 3 ): 324 – 329 . Google Scholar CrossRef Search ADS PubMed 78. Joshua AM , Ezzat S , Asa SL , Evans A , Broom R , Freeman M , Knox JJ . Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma . J Clin Endocrinol Metab . 2009 ; 94 ( 1 ): 5 – 9 . Google Scholar CrossRef Search ADS PubMed 79. Jimenez C , Cabanillas ME , Santarpia L , Jonasch E , Kyle KL , Lano EA , Matin SF , Nunez RF , Perrier ND , Phan A , Rich TA , Shah B , Williams MD , Waguespack SG . Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors . J Clin Endocrinol Metab . 2009 ; 94 ( 2 ): 386 – 391 . Google Scholar CrossRef Search ADS PubMed 80. ClinicalTrials.gov . Genetic analysis of pheochromocytomas, paragangliomas and associated conditions. ClinicalTrials.gov identifier: NCT03160274. Registered 19 October 2005. Updated 19 May 2017 . https://clinicaltrials.gov/ct2/show/NCT03160274. 81. Loriot C , Burnichon N , Gadessaud N , Vescovo L , Amar L , Libé R , Bertherat J , Plouin PF , Jeunemaitre X , Gimenez-Roqueplo AP , Favier J . Epithelial to mesenchymal transition is activated in metastatic pheochromocytomas and paragangliomas caused by SDHB gene mutations . J Clin Endocrinol Metab . 2012 ; 97 ( 6 ): E954 – E962 . Google Scholar CrossRef Search ADS PubMed 82. van Berkel A , Rao JU , Kusters B , Demir T , Visser E , Mensenkamp AR , van der Laak JA , Oosterwijk E , Lenders JW , Sweep FC , Wevers RA , Hermus AR , Langenhuijsen JF , Kunst DP , Pacak K , Gotthardt M , Timmers HJ . Correlation between in vivo 18F-FDG PET and immunohistochemical markers of glucose uptake and metabolism in pheochromocytoma and paraganglioma . J Nucl Med . 2014 ; 55 ( 8 ): 1253 – 1259 . Google Scholar CrossRef Search ADS PubMed 83. Chang CA , Pattison DA , Tothill RW , Kong G , Akhurst TJ , Hicks RJ , Hofman MS . (68)Ga-DOTATATE and (18)F-FDG PET/CT in paraganglioma and pheochromocytoma: utility, patterns and heterogeneity . Cancer Imaging . 2016 ; 16 ( 1 ): 22 . Google Scholar CrossRef Search ADS PubMed 84. Mardis ER , Ding L , Dooling DJ , Larson DE , McLellan MD , Chen K , Koboldt DC , Fulton RS , Delehaunty KD , McGrath SD , Fulton LA , Locke DP , Magrini VJ , Abbott RM , Vickery TL , Reed JS , Robinson JS , Wylie T , Smith SM , Carmichael L , Eldred JM , Harris CC , Walker J , Peck JB , Du F , Dukes AF , Sanderson GE , Brummett AM , Clark E , McMichael JF , Meyer RJ , Schindler JK , Pohl CS , Wallis JW , Shi X , Lin L , Schmidt H , Tang Y , Haipek C , Wiechert ME , Ivy JV , Kalicki J , Elliott G , Ries RE , Payton JE , Westervelt P , Tomasson MH , Watson MA , Baty J , Heath S , Shannon WD , Nagarajan R , Link DC , Walter MJ , Graubert TA , DiPersio JF , Wilson RK , Ley TJ . Recurring mutations found by sequencing an acute myeloid leukemia genome . N Engl J Med . 2009 ; 361 ( 11 ): 1058 – 1066 . Google Scholar CrossRef Search ADS PubMed 85. Parsons DW , Jones S , Zhang X , Lin JC , Leary RJ , Angenendt P , Mankoo P , Carter H , Siu IM , Gallia GL , Olivi A , McLendon R , Rasheed BA , Keir S , Nikolskaya T , Nikolsky Y , Busam DA , Tekleab H , Diaz LA Jr , Hartigan J , Smith DR , Strausberg RL , Marie SK , Shinjo SM , Yan H , Riggins GJ , Bigner DD , Karchin R , Papadopoulos N , Parmigiani G , Vogelstein B , Velculescu VE , Kinzler KW . An integrated genomic analysis of human glioblastoma multiforme . Science . 2008 ; 321 ( 5897 ): 1807 – 1812 . Google Scholar CrossRef Search ADS PubMed 86. Dang L , White DW , Gross S , Bennett BD , Bittinger MA , Driggers EM , Fantin VR , Jang HG , Jin S , Keenan MC , Marks KM , Prins RM , Ward PS , Yen KE , Liau LM , Rabinowitz JD , Cantley LC , Thompson CB , Vander Heiden MG , Su SM . Cancer-associated IDH1 mutations produce 2-hydroxyglutarate . Nature . 2009 ; 462 ( 7274 ): 739 – 744 . Google Scholar CrossRef Search ADS PubMed 87. Andronesi OC , Kim GS , Gerstner E , Batchelor T , Tzika AA , Fantin VR , Vander Heiden MG , Sorensen AG . Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy . Sci Transl Med . 2012 ; 4 ( 116 ): 116ra4 . Google Scholar CrossRef Search ADS PubMed 88. Choi C , Ganji SK , DeBerardinis RJ , Hatanpaa KJ , Rakheja D , Kovacs Z , Yang XL , Mashimo T , Raisanen JM , Marin-Valencia I , Pascual JM , Madden CJ , Mickey BE , Malloy CR , Bachoo RM , Maher EA . 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas . Nat Med . 2012 ; 18 ( 4 ): 624 – 629 . Google Scholar CrossRef Search ADS PubMed 89. Gross S , Cairns RA , Minden MD , Driggers EM , Bittinger MA , Jang HG , Sasaki M , Jin S , Schenkein DP , Su SM , Dang L , Fantin VR , Mak TW . Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations . J Exp Med . 2010 ; 207 ( 2 ): 339 – 344 . Google Scholar CrossRef Search ADS PubMed 90. Pope WB , Prins RM , Albert Thomas M , Nagarajan R , Yen KE , Bittinger MA , Salamon N , Chou AP , Yong WH , Soto H , Wilson N , Driggers E , Jang HG , Su SM , Schenkein DP , Lai A , Cloughesy TF , Kornblum HI , Wu H , Fantin VR , Liau LM . Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy . J Neurooncol . 2012 ; 107 ( 1 ): 197 – 205 . Google Scholar CrossRef Search ADS PubMed 91. Lu C , Ward PS , Kapoor GS , Rohle D , Turcan S , Abdel-Wahab O , Edwards CR , Khanin R , Figueroa ME , Melnick A , Wellen KE , O’Rourke DM , Berger SL , Chan TA , Levine RL , Mellinghoff IK , Thompson CB . IDH mutation impairs histone demethylation and results in a block to cell differentiation . Nature . 2012 ; 483 ( 7390 ): 474 – 478 . Google Scholar CrossRef Search ADS PubMed 92. Xu W , Yang H , Liu Y , Yang Y , Wang P , Kim SH , Ito S , Yang C , Wang P , Xiao MT , Liu LX , Jiang WQ , Liu J , Zhang JY , Wang B , Frye S , Zhang Y , Xu YH , Lei QY , Guan KL , Zhao SM , Xiong Y . Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases . Cancer Cell . 2011 ; 19 ( 1 ): 17 – 30 . Google Scholar CrossRef Search ADS PubMed 93. Zhao S , Lin Y , Xu W , Jiang W , Zha Z , Wang P , Yu W , Li Z , Gong L , Peng Y , Ding J , Lei Q , Guan KL , Xiong Y . Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha . Science . 2009 ; 324 ( 5924 ): 261 – 265 . Google Scholar CrossRef Search ADS PubMed 94. Chowdhury R , Yeoh KK , Tian YM , Hillringhaus L , Bagg EA , Rose NR , Leung IK , Li XS , Woon EC , Yang M , McDonough MA , King ON , Clifton IJ , Klose RJ , Claridge TD , Ratcliffe PJ , Schofield CJ , Kawamura A . The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases . EMBO Rep . 2011 ; 12 ( 5 ): 463 – 469 . Google Scholar CrossRef Search ADS PubMed 95. Jin G , Reitman ZJ , Spasojevic I , Batinic-Haberle I , Yang J , Schmidt-Kittler O , Bigner DD , Yan H . 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations . PLoS One . 2011 ; 6 ( 2 ): e16812 . Google Scholar CrossRef Search ADS PubMed 96. Metellus P , Colin C , Taieb D , Guedj E , Nanni-Metellus I , de Paula AM , Colavolpe C , Fuentes S , Dufour H , Barrie M , Chinot O , Ouafik L , Figarella-Branger D . IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients . J Neurooncol . 2011 ; 105 ( 3 ): 591 – 600 . Google Scholar CrossRef Search ADS PubMed 97. Williams SC , Karajannis MA , Chiriboga L , Golfinos JG , von Deimling A , Zagzag D . R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1α upregulation in adult glioma . Acta Neuropathol . 2011 ; 121 ( 2 ): 279 – 281 . Google Scholar CrossRef Search ADS PubMed 98. Burr SP , Costa AS , Grice GL , Timms RT , Lobb IT , Freisinger P , Dodd RB , Dougan G , Lehner PJ , Frezza C , Nathan JA . Mitochondrial protein lipoylation and the 2-oxoglutarate dehydrogenase complex controls HIF1α stability in aerobic conditions . Cell Metab . 2016 ; 24 ( 5 ): 740 – 752 . Google Scholar CrossRef Search ADS PubMed 99. Lee G , Won HS , Lee YM , Choi JW , Oh TI , Jang JH , Choi DK , Lim BO , Kim YJ , Park JW , Puigserver P , Lim JH . Oxidative dimerization of PHD2 is responsible for its inactivation and contributes to metabolic reprogramming via HIF-1α activation . Sci Rep . 2016 ; 6 : 18928 . Google Scholar CrossRef Search ADS PubMed 100. Figueroa ME , Abdel-Wahab O , Lu C , Ward PS , Patel J , Shih A , Li Y , Bhagwat N , Vasanthakumar A , Fernandez HF , Tallman MS , Sun Z , Wolniak K , Peeters JK , Liu W , Choe SE , Fantin VR , Paietta E , Löwenberg B , Licht JD , Godley LA , Delwel R , Valk PJ , Thompson CB , Levine RL , Melnick A . Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation . Cancer Cell . 2010 ; 18 ( 6 ): 553 – 567 . Google Scholar CrossRef Search ADS PubMed 101. Turcan S , Rohle D , Goenka A , Walsh LA , Fang F , Yilmaz E , Campos C , Fabius AW , Lu C , Ward PS , Thompson CB , Kaufman A , Guryanova O , Levine R , Heguy A , Viale A , Morris LG , Huse JT , Mellinghoff IK , Chan TA . IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype . Nature . 2012 ; 483 ( 7390 ): 479 – 483 . Google Scholar CrossRef Search ADS PubMed 102. Birendra KC , DiNardo CD . Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120 . Clin Lymphoma Myeloma Leuk . 2016 ; 16 ( 8 ): 460 – 465 . Google Scholar CrossRef Search ADS PubMed 103. Kats LM , Vervoort SJ , Cole R , Rogers AJ , Gregory GP , Vidacs E , Li J , Nagaraja R , Yen KE , Johnstone RW . A pharmacogenomic approach validates AG-221 as an effective and on-target therapy in IDH2 mutant AML . Leukemia . 2017 ; 31 ( 6 ): 1466 – 1470 . Google Scholar CrossRef Search ADS PubMed 104. Stein EM . IDH2 inhibition in AML: finally progress ? Best Pract Res Clin Haematol . 2015 ; 28 ( 2-3 ): 112 – 115 . Google Scholar CrossRef Search ADS PubMed 105. Kerrigan JF , Aleck KA , Tarby TJ , Bird CR , Heidenreich RA . Fumaric aciduria: clinical and imaging features . Ann Neurol . 2000 ; 47 ( 5 ): 583 – 588 . Google Scholar CrossRef Search ADS PubMed 106. Tomlinson IP , Alam NA , Rowan AJ , Barclay E , Jaeger EE , Kelsell D , Leigh I , Gorman P , Lamlum H , Rahman S , Roylance RR , Olpin S , Bevan S , Barker K , Hearle N , Houlston RS , Kiuru M , Lehtonen R , Karhu A , Vilkki S , Laiho P , Eklund C , Vierimaa O , Aittomäki K , Hietala M , Sistonen P , Paetau A , Salovaara R , Herva R , Launonen V , Aaltonen LA ; Multiple Leiomyoma Consortium . Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer . Nat Genet . 2002 ; 30 ( 4 ): 406 – 410 . Google Scholar CrossRef Search ADS PubMed 107. Frezza C , Pollard PJ , Gottlieb E . Inborn and acquired metabolic defects in cancer . J Mol Med (Berl) . 2011 ; 89 ( 3 ): 213 – 220 . Google Scholar CrossRef Search ADS PubMed 108. Ha YS , Chihara Y , Yoon HY , Kim YJ , Kim TH , Woo SH , Yun SJ , Kim IY , Hirao Y , Kim WJ . Downregulation of fumarate hydratase is related to tumorigenesis in sporadic renal cell cancer . Urol Int . 2013 ; 90 ( 2 ): 233 – 239 . Google Scholar CrossRef Search ADS PubMed 109. Carvajal-Carmona LG , Alam NA , Pollard PJ , Jones AM , Barclay E , Wortham N , Pignatelli M , Freeman A , Pomplun S , Ellis I , Poulsom R , El-Bahrawy MA , Berney DM , Tomlinson IP . Adult Leydig cell tumors of the testis caused by germline fumarate hydratase mutations . J Clin Endocrinol Metab . 2006 ; 91 ( 8 ): 3071 – 3075 . Google Scholar CrossRef Search ADS PubMed 110. Fieuw A , Kumps C , Schramm A , Pattyn F , Menten B , Antonacci F , Sudmant P , Schulte JH , Van Roy N , Vergult S , Buckley PG , De Paepe A , Noguera R , Versteeg R , Stallings R , Eggert A , Vandesompele J , De Preter K , Speleman F . Identification of a novel recurrent 1q42.2-1qter deletion in high risk MYCN single copy 11q deleted neuroblastomas . Int J Cancer . 2012 ; 130 ( 11 ): 2599 – 2606 . Google Scholar CrossRef Search ADS PubMed 111. Clark GR , Sciacovelli M , Gaude E , Walsh DM , Kirby G , Simpson MA , Trembath RC , Berg JN , Woodward ER , Kinning E , Morrison PJ , Frezza C , Maher ER . Germline FH mutations presenting with pheochromocytoma . J Clin Endocrinol Metab . 2014 ; 99 ( 10 ): E2046 – E2050 . Google Scholar CrossRef Search ADS PubMed 112. Picaud S , Kavanagh KL , Yue WW , Lee WH , Muller-Knapp S , Gileadi O , Sacchettini J , Oppermann U . Structural basis of fumarate hydratase deficiency . J Inherit Metab Dis . 2011 ; 34 ( 3 ): 671 – 676 . Google Scholar CrossRef Search ADS PubMed 113. Frezza C , Zheng L , Folger O , Rajagopalan KN , MacKenzie ED , Jerby L , Micaroni M , Chaneton B , Adam J , Hedley A , Kalna G , Tomlinson IP , Pollard PJ , Watson DG , Deberardinis RJ , Shlomi T , Ruppin E , Gottlieb E . Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase . Nature . 2011 ; 477 ( 7363 ): 225 – 228 . Google Scholar CrossRef Search ADS PubMed 114. Adam J , Yang M , Bauerschmidt C , Kitagawa M , O’Flaherty L , Maheswaran P , Özkan G , Sahgal N , Baban D , Kato K , Saito K , Iino K , Igarashi K , Stratford M , Pugh C , Tennant DA , Ludwig C , Davies B , Ratcliffe PJ , El-Bahrawy M , Ashrafian H , Soga T , Pollard PJ . A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia . Cell Reports . 2013 ; 3 ( 5 ): 1440 – 1448 . Google Scholar CrossRef Search ADS PubMed 115. Zheng L , MacKenzie ED , Karim SA , Hedley A , Blyth K , Kalna G , Watson DG , Szlosarek P , Frezza C , Gottlieb E . Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells . Cancer Metab . 2013 ; 1 ( 1 ): 12 . Google Scholar CrossRef Search ADS PubMed 116. Xiao M , Yang H , Xu W , Ma S , Lin H , Zhu H , Liu L , Liu Y , Yang C , Xu Y , Zhao S , Ye D , Xiong Y , Guan KL . Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors . Genes Dev . 2012 ; 26 ( 12 ): 1326 – 1338 . Google Scholar CrossRef Search ADS PubMed 117. Laukka T , Mariani CJ , Ihantola T , Cao JZ , Hokkanen J , Kaelin WG Jr , Godley LA , Koivunen P . Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes . J Biol Chem . 2016 ; 291 ( 8 ): 4256 – 4265 . Google Scholar CrossRef Search ADS PubMed 118. Linehan WM , Spellman PT , Ricketts CJ , Creighton CJ , Fei SS , Davis C , Wheeler DA , Murray BA , Schmidt L , Vocke CD , Peto M , Al Mamun AA , Shinbrot E , Sethi A , Brooks S , Rathmell WK , Brooks AN , Hoadley KA , Robertson AG , Brooks D , Bowlby R , Sadeghi S , Shen H , Weisenberger DJ , Bootwalla M , Baylin SB , Laird PW , Cherniack AD , Saksena G , Haake S , Li J , Liang H , Lu Y , Mills GB , Akbani R , Leiserson MD , Raphael BJ , Anur P , Bottaro D , Albiges L , Barnabas N , Choueiri TK , Czerniak B , Godwin AK , Hakimi AA , Ho TH , Hsieh J , Ittmann M , Kim WY , Krishnan B , Merino MJ , Mills Shaw KR , Reuter VE , Reznik E , Shelley CS , Shuch B , Signoretti S , Srinivasan R , Tamboli P , Thomas G , Tickoo S , Burnett K , Crain D , Gardner J , Lau K , Mallery D , Morris S , Paulauskis JD , Penny RJ , Shelton C , Shelton WT , Sherman M , Thompson E , Yena P , Avedon MT , Bowen J , Gastier-Foster JM , Gerken M , Leraas KM , Lichtenberg TM , Ramirez NC , Santos T , Wise L , Zmuda E , Demchok JA , Felau I , Hutter CM , Sheth M , Sofia HJ , Tarnuzzer R , Wang Z , Yang L , Zenklusen JC , Zhang J , Ayala B , Baboud J , Chudamani S , Liu J , Lolla L , Naresh R , Pihl T , Sun Q , Wan Y , Wu Y , Ally A , Balasundaram M , Balu S , Beroukhim R , Bodenheimer T , Buhay C , Butterfield YS , Carlsen R , Carter SL , Chao H , Chuah E , Clarke A , Covington KR , Dahdouli M , Dewal N , Dhalla N , Doddapaneni HV , Drummond JA , Gabriel SB , Gibbs RA , Guin R , Hale W , Hawes A , Hayes DN , Holt RA , Hoyle AP , Jefferys SR , Jones SJ , Jones CD , Kalra D , Kovar C , Lewis L , Li J , Ma Y , Marra MA , Mayo M , Meng S , Meyerson M , Mieczkowski PA , Moore RA , Morton D , Mose LE , Mungall AJ , Muzny D , Parker JS , Perou CM , Roach J , Schein JE , Schumacher SE , Shi Y , Simons JV , Sipahimalani P , Skelly T , Soloway MG , Sougnez C , Tam A , Tan D , Thiessen N , Veluvolu U , Wang M , Wilkerson MD , Wong T , Wu J , Xi L , Zhou J , Bedford J , Chen F , Fu Y , Gerstein M , Haussler D , Kasaian K , Lai P , Ling S , Radenbaugh A , Van Den Berg D , Weinstein JN , Zhu J , Albert M , Alexopoulou I , Andersen JJ , Auman JT , Bartlett J , Bastacky S , Bergsten J , Blute ML , Boice L , Bollag RJ , Boyd J , Castle E , Chen YB , Cheville JC , Curley E , Davies B , DeVolk A , Dhir R , Dike L , Eckman J , Engel J , Harr J , Hrebinko R , Huang M , Huelsenbeck-Dill L , Iacocca M , Jacobs B , Lobis M , Maranchie JK , McMeekin S , Myers J , Nelson J , Parfitt J , Parwani A , Petrelli N , Rabeno B , Roy S , Salner AL , Slaton J , Stanton M , Thompson RH , Thorne L , Tucker K , Weinberger PM , Winemiller C , Zach LA , Zuna R ; Cancer Genome Atlas Research Network . Comprehensive molecular characterization of papillary renal-cell carcinoma . N Engl J Med . 2016 ; 374 ( 2 ): 135 – 145 . Google Scholar CrossRef Search ADS PubMed 119. Isaacs JS , Jung YJ , Mole DR , Lee S , Torres-Cabala C , Chung YL , Merino M , Trepel J , Zbar B , Toro J , Ratcliffe PJ , Linehan WM , Neckers L . HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability . Cancer Cell . 2005 ; 8 ( 2 ): 143 – 153 . Google Scholar CrossRef Search ADS PubMed 120. Cascón A , Comino-Méndez I , Currás-Freixes M , de Cubas AA , Contreras L , Richter S , Peitzsch M , Mancikova V , Inglada-Pérez L , Pérez-Barrios A , Calatayud M , Azriel S , Villar-Vicente R , Aller J , Setién F , Moran S , Garcia JF , Río-Machín A , Letón R , Gómez-Graña Á , Apellániz-Ruiz M , Roncador G , Esteller M , Rodríguez-Antona C , Satrústegui J , Eisenhofer G , Urioste M , Robledo M . Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene . J Natl Cancer Inst . 2015 ; 107 ( 5 ). 121. Pan Y , Mansfield KD , Bertozzi CC , Rudenko V , Chan DA , Giaccia AJ , Simon MC . Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro . Mol Cell Biol . 2007 ; 27 ( 3 ): 912 – 925 . Google Scholar CrossRef Search ADS PubMed 122. Philip B , Ito K , Moreno-Sánchez R , Ralph SJ . HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression . Carcinogenesis . 2013 ; 34 ( 8 ): 1699 – 1707 . Google Scholar CrossRef Search ADS PubMed

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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Feb 1, 2018

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