Pheochromocytoma/Paraganglioma: A Poster Child for Cancer Metabolism
J Clin Endocrinol Metab, May
Pheochromocytoma/Paraganglioma: A Poster Child for Cancer Metabolism
Sergei G. Tevosian 0
Hans K. Ghayee 1 2
0 Department of Physiological Sciences, University of Florida , Gainesville, Florida 32610 , USA
1 Department of Medicine, Division of Endocrinology, University of Florida , Gainesville, Florida 32610 , USA
2 Malcom Randall VA Medical Center , Gainesville, Florida 32608 , USA
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. (J Clin Endocrinol Metab 103: 1779-1789, 2018)
Ihis novel Strange Case of Dr. Jekyll and Mr. Hyde, the
n 1886, the year that Robert Louis Stevenson published
first case of pheochromocytoma (PCC) was documented
in Germany and described an 18-year-old woman with
hypertensive crisis due to bilateral adrenal tumors (
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) (
). 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
), 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 (
). 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
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;
(SDHx) complex in hereditary PCC/PGLs. This discovery
became the first documented case that directly linked
defective mitochondrial protein with cancer predisposition (
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 (
). 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 (
). This advancement
in PCC/PGL imaging has come about through
understanding of the alteration in glucose metabolism in these
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 (
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 (
) (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.
Depending on the type of the mutation, PCC/PGLs
have distinctive gene expression profiles that assemble
(cluster) in two so-called cluster groups (
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
). Most of the tumors that comprise
cluster 1 are PGLs (
). 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 (
). 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
). 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 (
). The third cluster is
associated with an expression of the Mastermind-like 3
(MAML3)?fusion genes and the fourth is a cortical
admixture phenotype (
). 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
). 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
). 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
protooncogenic function for metabolic products. Germline
mutations in the SDHD gene were the first
mitochondrial enzyme mutations documented in cancer (
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 (
). Mutations in SDH are found in
renal carcinomas (
), T-cell leukemia (
gastrointestinal stromal tumors (
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 (
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
SDHdeficient cells through pyruvate carboxylation. This
metabolic reprogramming presents a vulnerability that
could be explored to target tumors carrying SDHx
Inducible transcription factors [hypoxia-inducible
factor (HIF)a/b 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
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
). 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 (
Succinate accumulation resulting from SDH deficiency
is the hallmark feature of SDH-deficient cells. Similar
to 2HG oncometabolite, a product of the IDH
gain-offunction mutations (discussed later in this article),
succinate-mediated inhibition targets a-ketoglutarate
(aKG)-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 (
). HIFa is continuously
synthesized; however, under normoxic conditions,
PHDmediated 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
HIF1a that escapes VHL recognition. Thus, hypoxia
protects HIFa from being degraded and the unmodified
molecule translocates to the nucleus, where it forms a
transcriptionally active HIF heterodimer with a stable
HIF1b subunit. The low affinity of PHDs for oxygen
makes them a reliable oxygen sensor (
inhibition by succinate leads to formation of an active
HIF dimer even in the presence of abundant oxygen, a
condition known as pseudohypoxia (
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 (
Activation of HIF and the pseudohypoxia pathway
appears to be particularly important in SDH-driven PGL/
). 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
). 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 (
). 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-2deoxy-D-glucose observed in pseudohypoxic tumors is
due to an elevated expression of glucose transporters and
other glycolytic enzymes integral to glucose metabolism
). 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 (
). It has been reported that 18F-
fluoro-Ldihydroxyphenylalanine 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 (
). In addition to SDH, genes encoding
the other components of oxidative respiratory chain are
dysregulated, contributing to the overall mitochondrial
). In summary, the pseudohypoxia
pathway is an essential component of SDH-mediated
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 (
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 (
). 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
aKG, the R132 mutants are neomorphs that acquired a
new function to convert aKG (also known as
2-oxoglutarate) to a chiral compound, D-2-hydroxyglutarate
) (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
). 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
followup of these tumors (
). 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 aKG into D-2HG led to the idea that enzymes
relying on aKG for their activity could be affected.
Several reports have provided evidence that 2HG can
inhibit various aKG-dependent dioxygenase enzymes
). Specifically, it has been proposed that 2HG is an
inhibitor of PHD2, which targets HIF1a for degradation
and that the increase in HIF1a level in IDH-null cells is
the cancer culprit (
). However, there is no clear
hypoxic signature in IDH-driven tumors, and a link
between D-2HG, PHD2 inhibition, and HIF1a
stabilization was generally not supported (
). Only the
L isoform of 2HG appears to inhibit PHD activity (
). 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 (
Given the close relationship among succinate,
isocitrate, aKG, 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 aKG-dependent enzymes, the
teneleven translocation (TET) family, was confirmed in
several independent studies (
92, 100, 101
). TET proteins
produce 50-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
lossof-function mutations in a large AML cohort (
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 (
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 (
In contrast, loss of heterozygosity in patients carrying
germline FH mutations causes hereditary leiomyomatosis
and renal cell cancer (
). FH is also
downregulated in renal carcinomas (108), Leydig cell tumors
), and, not dissimilar to IDH, deleted in neural
tumors, neuroblastomas (
). Most importantly, FH
mutations have been isolated in PCC/PGLs (
underscoring the propensity of the mutations in
TCAcycle 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
). 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 (
). 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 (
It was also proposed that fumarate could inhibit other
aKG-dependent dehydrogenases, specifically PHD, and
induce pseudohypoxia acting through HIFs (
Malate dehydrogenase 2
Recently, Casco? n et al. (
) 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 HIFa (
). 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.
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, aKG, 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.
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.
Correspondence and Reprint Requests: Hans K. Ghayee,
DO, Malcom Randall VA Medical Center, University of
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 .
2. Pick L. Das Ganglioma embryonale sympathicum (Sympathoma embryonale), eine typische bo? sartige 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 .
4. Otto AM . Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism . Cancer Metab . 2016 ; 4 ( 1 ): 5 .
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 .
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 .
7. Young WF Jr. Clinical practice. The incidentally discovered adrenal mass . N Engl J Med . 2007 ; 356 ( 6 ): 601 - 610 .
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 .
9. Ta??eb D , Pacak K . New insights into the nuclear imaging phenotypes of cluster 1 pheochromocytoma and paraganglioma . Trends Endocrinol Metab . 2017 ; 28 ( 11 ): 807 - 817 .
10. Favier J , Brie`re JJ, Burnichon N , Rivie`re J , Vescovo L , Benit P , Giscos-Douriez I , De Reynie`s A , Bertherat J , Badoual C , Tissier F , Amar L , Libe? R, Plouin PF , Jeunemaitre X , Rustin P , GimenezRoqueplo AP . The Warburg effect is genetically determined in inherited pheochromocytomas . PLoS One . 2009 ; 4 ( 9 ): e7094 .
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 .
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 .
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 .
14. Comino-Me?ndez I , Tejera A ?M, Curr a?s- Freixes M , Remacha L , Gonzalvo P , Tonda R , Leto? n R , Blasco MA , Robledo M , Casco? n A. ATRX driver mutation in a composite malignant pheochromocytoma . Cancer Genet . 2016 ; 209 ( 6 ): 272 - 277 .
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 .
16. Castro-Vega LJ , Buffet A , De Cubas AA , Casco? n A , Menara M , Khalifa E , Amar L , Azriel S , Bourdeau I , Chabre O , Curr a?s- Freixes M , Franco-Vidal V , Guillaud-Bataille M , Simian C , Morin A , Leto? n R , Go? mez -Gran~a 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 .
17. Zhuang Z , Yang C , Lorenzo F , Merino M , Fojo T , Kebebew E , Popovic V , Stratakis CA , Prchal JT , Pacak K. Somatic HIF2A gainof -function mutations in paraganglioma with polycythemia . N Engl J Med . 2012 ; 367 ( 10 ): 922 - 930 .
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 .
19. Comino-Me?ndez I , de Cubas AA , Bernal C , A?lvarez-Escol a? C, S a?nchez- Malo C , Ram??rez- Tortosa CL , Pedrinaci S , Rapizzi E , Ercolino T , Bernini G , Bacca A , Leto? n R , Pita G , Alonso MR , Leandro-Garc??a LJ, G o?mez-Gra~na A , Inglada- Pe?rez L , Mancikova V , Rodr?? guez-Antona C , Mannelli M , Robledo M , Casco? n A. Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis . Hum Mol Genet . 2013 ; 22 ( 11 ): 2169 - 2176 .
20. Crona J , Delgado Verdugo A , Maharjan R , St a?lberg P, Granberg D , Hellman P , Bj o?rklund P. Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing . J Clin Endocrinol Metab . 2013 ; 98 ( 7 ): E1266 - E1271 .
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 .
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 .
23. Comino-Me?ndez I , Gracia-Azn a?rez FJ , Schiavi F , Landa I , Leandro-Garc??a LJ , Leto? n R , Honrado E , Ramos-Medina R , Caronia D , Pita G , Go? mez-Gran~a A , de Cubas AA , Inglada- Pe?rez L , Maliszewska A , Taschin E , Bobisse S , Pica G , Loli P , Hern a? ndez-Lavado R , D??az JA, G o? mez- Morales M , Gonz a?lezNeira A , Roncador G , Rodr?? guez-Antona C , Ben??tez J , Mannelli M , Opocher G , Robledo M , Casco? n A. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma . Nat Genet . 2011 ; 43 ( 7 ): 663 - 667 .
24. Cascon A , Comino-Me?ndez I , Curr a?s- Freixes M , de Cubas AA , Contreras L , Richter S , Peitzsch M , Mancikova V , Inglada-Pere? z L , Pe? rez-Barrios A , Calatayud M , Azriel S , Villar-Vicente R , Aller J , Setie? n F , Moran S , Garcia JF , R??o-Mach??n A, Let o?n R, Go? mezGran~a A? , Apell a?niz- Ruiz M , Roncador G , Esteller M , Rodr??guezAntona C, Satru? stegui 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 .
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 .
27. Hope DG , Mulvihill JJ . Malignancy in neurofibromatosis . Adv Neurol . 1981 ; 29 : 33 - 56 .
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 .
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/paragangliomapolycythemia . J Mol Med (Berl). 2015 ; 93 ( 1 ): 93 - 104 .
30. Ladroue C , Carcenac R , Leporrier M , Gad S , Le Hello C , Galateau-Salle F , Feunteun J , Pouysse?gur J , Richard S , Gardie B. PHD2 mutation and congenital erythrocytosis with paraganglioma . N Engl J Med . 2008 ; 359 ( 25 ): 2685 - 2692 .
31. Burnichon N , Brie`re JJ, Libe? R, Vescovo L , Rivie`re J , Tissier F , Jouanno E , Jeunemaitre X , B e?nit 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 .
32. Bayley JP , Kunst HP , Cascon A , Sampietro ML , Gaal J , Korpershoek E , Hinojar-Gutierrez A , Timmers HJ , Hoefsloot LH , Hermsen MA , Sua?rez 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 .
33. Astuti D , Latif F , Dallol A , Dahia PL , Douglas F , George E , Sko? ldberg 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 .
34. Niemann S , Mu? ller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3 . Nat Genet . 2000 ; 26 ( 3 ): 268 - 270 .
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 .
36. Neumann HP , Eng C , Mulligan LM , Glavac D , Z a? uner 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 .
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 .
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 .
39. Letouze ? 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 Reynie`s A , Gimenez-Roqueplo AP , Favier J. SDH mutations establish a hypermethylator phenotype in paraganglioma . Cancer Cell . 2013 ; 23 ( 6 ): 739 - 752 .
40. Burnichon N , Vescovo L , Amar L , Libe? 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 .
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 , Nose? V, Li C , Stiles CDA . A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas . PLoS Genet . 2005 ; 1 ( 1 ): 72 - 80 .
42. Burnichon N , Casco? n A , Schiavi F , Morales NP , Comino-Me?ndez I , Abermil N , Inglada- Pe?rez L, de Cubas AA , Amar L , Barontini M , de Quir o?s SB, Bertherat J , Bignon YJ , Blok MJ , Bobisse S , Borrego S , Castellano M , Chanson P , Chiara MD , Corssmit EP , Giacche` M, de Krijger RR , Ercolino T , Girerd X , Go? mez-Garc??a EB, G o?mez- Gran~ a A , Guilhem I , Hes FJ , Honrado E , Korpershoek E , Lenders JW , Let o?n 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 .
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 .
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 .
45. Vanharanta S , Buchta M , McWhinney SR , Virta SK , Pe?zkowska M , Morrison CD , Lehtonen R , Januszewicz A , J a?rvinen 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 SDHBassociated heritable paraganglioma . Am J Hum Genet . 2004 ; 74 ( 1 ): 153 - 159 .
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 .
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 .
48. Janeway KA , Kim SY , Lodish M , Nose ? 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 .
49. Mu ? ller U. Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC) . Neurogenetics . 2011 ; 12 ( 3 ): 175 - 181 .
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 .
51. Bardella C , Pollard PJ , Tomlinson I. SDH mutations in cancer . Biochim Biophys Acta . 2011 ; 1807 (11): 1432 - 1443 .
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 .
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 .
54. Gimenez-Roqueplo AP , Favier J , Rustin P , Mourad JJ , Plouin PF , Corvol P , R o?tig 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 .
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 .
56. Wallace DC . Mitochondria and cancer . Nat Rev Cancer . 2012 ; 12 ( 10 ): 685 - 698 .
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 .
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 .
59. Bausch B , Schiavi F , Ni Y , Welander J , Patocs A , Ngeow J , Wellner U , Malinoc A , Taschin E , Barbon G , Lanza V , S o?derkvist 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 O ?, Boedeker CC , Weryha G , Racz K , Januszewicz A , Walz MK , Gimm O , Opocher G , Eng C , Neumann HPH ; EuropeanAmerican-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 .
60. Klein R , Lloyd R , Young W. Hereditary paragangliomapheochromocytoma 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 SDHdeficient cells by supporting aspartate biosynthesis . Nat Cell Biol . 2015 ; 17 ( 10 ): 1317 - 1326 .
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 .
63. Brie`re JJ, Favier J , Be?nit 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 .
64. Rodr?? guez-Cuevas S , L o? pez-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 .
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 .
66. Morin A , Letouze ? E, Gimenez-Roqueplo AP , Favier J . Oncometabolitesdriven tumorigenesis: from genetics to targeted therapy . Int J Cancer . 2014 ; 135 ( 10 ): 2237 - 2248 .
67. Pollard PJ , Brie`re 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 .
68. Yang M , Pollard PJ . Succinate: a new epigenetic hacker . Cancer Cell . 2013 ; 23 ( 6 ): 709 - 711 .
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 .
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 .
71. Kim WY , Kaelin WG . Role of VHL gene mutation in human cancer . J Clin Oncol . 2004 ; 22 ( 24 ): 4991 - 5004 .
72. Schofield CJ , Ratcliffe PJ . Oxygen sensing by HIF hydroxylases . Nat Rev Mol Cell Biol . 2004 ; 5 ( 5 ): 343 - 354 .
73. Gottlieb E , Tomlinson IP . Mitochondrial tumour suppressors: a genetic and biochemical update . Nat Rev Cancer . 2005 ; 5 ( 11 ): 857 - 866 .
74. Chandel NS , McClintock DS , Feliciano CE , Wood TM , Melendez JA , Rodriguez AM , Schumacker PT . Reactive oxygen species generated at mitochondrial complex III stabilize hypoxiainducible factor-1alpha during hypoxia: a mechanism of O2 sensing . J Biol Chem . 2000 ; 275 ( 33 ): 25130 - 25138 .
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 .
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 .
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 .
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 .
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 .
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 , Libe? 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 .
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 .
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 .
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 .
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 .
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 .
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 .
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 .
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 .
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 .
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 .
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 a-ketoglutarate-dependent dioxygenases . Cancer Cell . 2011 ; 19 ( 1 ): 17 - 30 .
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 .
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 .
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 .
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 .
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-1a upregulation in adult glioma . Acta Neuropathol . 2011 ; 121 ( 2 ): 279 - 281 .
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 HIF1a stability in aerobic conditions . Cell Metab . 2016 ; 24 ( 5 ): 740 - 752 .
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-1a activation . Sci Rep . 2016 ; 6 : 18928 .
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 , L o?wenberg 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 .
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 .
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 .
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 .
104. Stein EM . IDH2 inhibition in AML: finally progress? Best Pract Res Clin Haematol . 2015 ; 28 ( 2-3 ): 112 - 115 .
105. Kerrigan JF , Aleck KA , Tarby TJ , Bird CR , Heidenreich RA . Fumaric aciduria: clinical and imaging features . Ann Neurol . 2000 ; 47 ( 5 ): 583 - 588 .
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 , Aittom a?ki 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 .
107. Frezza C , Pollard PJ , Gottlieb E . Inborn and acquired metabolic defects in cancer . J Mol Med (Berl). 2011 ; 89 ( 3 ): 213 - 220 .
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 .
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 .
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 .
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 .
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 .
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 .
114. Adam J , Yang M , Bauerschmidt C , Kitagawa M , O'Flaherty L , Maheswaran P , O? zkan 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 .
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 .
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 a-KGdependent 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 .
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 .
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 .
120. Casco? n A , Comino-Me?ndez I , Curr a?s- Freixes M , de Cubas AA , Contreras L , Richter S , Peitzsch M , Mancikova V , Inglada- Pe?rez L , Pe? rez-Barrios A , Calatayud M , Azriel S , Villar-Vicente R , Aller J , Setie? n F , Moran S , Garcia JF , R??o- Mach??n A , Leto? n R , Go? mezGran~a A?, Apell a?niz- Ruiz M , Roncador G , Esteller M , Rodr??guezAntona C, Satru? stegui 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 .
122. Philip B , Ito K , Moreno-S a?nchez 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 .