Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC)
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- Müller, U. Neurogenetics (2011) 12: 175. doi:10.1007/s10048-011-0280-y
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Paragangliomas/pheochromocytomas (PGL/PCC) are tumors of the paraganglia. They can occur sporadically, as one sign in a hereditary (tumor) syndrome or as the only manifestation in hereditary PGL/PCC. To date, five forms of hereditary PGL/PCC have been described. They are inherited as autosomal dominant traits and are caused by mutations in genes required for structure and function of complex II of the respiratory chain (succinate-ubiquinone oxidoreductase, succinate dehydrogenase, SDH). Mutations in genes encoding the small subunits of SDH, i.e., SDHD and SDHC, cause PGL1 and PGL3. Mutations in the large subunit genes SDHB, SDHA (currently only one case), and in SDHAF2 cause PGL4, 5, and 2, respectively. This article gives an overview of PGL/PCC in the context of the anatomy and function of paraganglia. It describes SDH, the genes encoding SDH, and provides information on genetic mechanisms in hereditary PGL/PCC. A model is proposed to explain exclusive paternal inheritance and loss of the maternal (putatively imprinted) allele as a prerequisite for tumor formation in PGLs 1 and 2.
KeywordsHereditary paraganglioma/pheochromocytomaMaternal imprintingTumorigenesisCellular hypoxiaSDHASDHBSDHCSDHDSDHAF2Succinate-ubiquinone oxidoreductaseComplex IIPartial imprinting
Paragangliomas (PGLs) are highly vascularized, usually benign tumors of the paraganglia. Paraganglia derive from the neuroectoderm and can be divided into non-chromaffin and chromaffin forms. Non-chromaffin paraganglia and the PGLs derived from them are associated with the parasympathetic nervous system and chromaffin paraganglia as well as chromaffin PGLs are components of the sympathetic nervous system.
Parasympathetic paraganglia (Fig. 1)
paraganglion (glomus) caroticum at the bifurcation of the carotis,
paraganglion (glomus) tympanicum,
paraganglion (glomus) jugulare at the jugular vein,
- superior and inferior paraganglion (glomus) laryngeum. The former is adjacent to thyroid cartilage in close proximity to superior laryngeal artery and nerve, the latter in close proximity and superior to the glottis.
Of these paraganglia, the role of the carotid body (glomus caroticum) is best understood. It functions as oxygen and, to a lesser extent, as carbon dioxide sensor and regulates the oxygen supply in the body. Its receptors are activated by hypoxia, pH, and temperature . The carotid body is composed of two cell types, glomus type I (“chief”) cells and glomus type II (sustentacular) cells. PGLs originate from “chief” cells.
Sympathetic paraganglia (Fig. 1)
Sympathetic paraganglia are chromaffin tissues and frequently secrete catecholamines. The adrenal medulla is the most important sympathetic paraganglion during postnatal life. Via secretion of catecholamines, mainly epinephrine (adrenaline) and norepinephrine (noradrenaline), the adrenal medulla regulates blood pressure, heart rate, blood glucose level, and plays an important role in stress situations. During embryonic life, the organ of Zuckerkandl (paraganglion aorticum abdominale) fulfills these roles. The paraganglion aorticum abdominale is located at the bifurcation of the inferior mesenteric artery at the abdominal aorta. While this tissue is well-differentiated and functional during prenatal life, it degenerates towards birth. Its functions are then taken over by the adrenal medulla and other sympathetic paraganglia of thorax and abdomen.
Tumors arising from paraganglia can be clinically divided into neuroendocrine and non-endocrine tumors. Neuroendocrine tumors primarily originate from sympathetic paraganglia, mainly the adrenal medulla, and are referred to as pheochromocytomas (PCCs) . The term pheochromocytoma is usually used to describe all chromaffin, endocrinologically active PGLs. However, some authors only classify chromaffin catecholamine-secreting adrenal tumors as “pheochromocytomas” and refer to other chromaffin, catecholamine-secreting tumors as “secreting paragangliomas” . According to the recommendations of the National Cancer Institute (http://cip.cancer.gov/dictionary/?CdrID=390305), only adrenal PGLs are referred to as PCCs. All other paraganglia-derived tumors are called either PGLs, glomus tumors, or chemodectomas. Non-endocrine PGLs are most frequently derived from parasympathetic paraganglia of the head and neck. They can be clinically further subdivided based on their location and include carotid body PGLs, tympanic and jugular PGLs, laryngeal PGLs, nasopharyngeal, and orbital PGLs. Clinically, tympanic and jugular PGLs are sometimes hard to differentiate and therefore are referred to as temporal PGLs. In rare instances, secretory parasympathetic PGLs have been observed.
Paragangliomas/pheochromocytomas can arise sporadically, occur as one of several signs within a hereditary (tumor-) syndrome or may be transmitted as the only trait in families (hereditary PGLs). Sporadic PGLs can be caused by low oxygen concentrations in the tidal air. Thus, the prevalence of PGLs is significantly increased in people living at high altitudes such as the Andes as compared to persons living at sea level . Syndromic occurrence of PGLs/PCCs is found in neurofibromatosis 1, von Hippel–Lindau syndrome, and multiple endocrine neoplasia 2 [5, 6]. The hereditary PGLs/PCCs are a genetically heterogeneous group of tumor syndromes that present with PGL and/or PCC as the only sign.
Hereditary PGL/PCC and succinate ubiquinone-oxidoreductase
Succinate–ubiquinone (succinate-coenzyme Q) oxidoreductase is composed of four subunits, SDHA, SDHB, SDHC, and SDHD (Fig. 2). Subunits SDHA (flavoprotein subunit) and SDHB (iron-sulfur protein subunit) have catalytic function. They are anchored in the inner mitochondrial membrane by the smaller subunits SDHC and SDHD. An additional protein, SDHAF2 (SDH5) is required for flavination of SDHA. SDHA is the largest subunit of succinate-ubiquinone oxidoreductase (72.692 kDa). It consists of 664 amino acids. SDHB is a polypeptide of 31.63 KDa and 280 amino acids. The smaller subunits SDHC and SDHD are polypeptides of 18.61 kDa (169 amino acids) and of 17.043 kDa (159 amino acids), respectively. SDHAF2 (succinate dehydrogenase complex assembly factor 2) is a polypeptide of 19.599 kDa, composed of 166 amino acids.
SDHA catalyzes the conversion of succinate to fumarate within the citric acid cycle (succinate + ubiquinone = fumarate + ubiquinol). This reaction also generates FADH2 from FAD. As part of the respiratory chain electrons from FADH2 are transferred to the SDHB subunit and finally to ubiquinone via the SDHC/SDHD subunits. Interaction of SDHA with SDHAF2 is required for FAD attachment.
The gene SDHA is located on chromosome 5 (5p15.33) and composed of 15 exons. SDHB is on chromosome 1 (1p36.13) and comprises eight exons. SDHC (six exons) and SDHD (four exons) are on chromosome 1 (1q23.3), and on chromosome 11 (11q23.1), respectively. SDHAF2 (SDH5) consists of four exons in 11q12.2 (for genes, their products and location see: http://www.ncbi.nlm.nih.gov)
Paragangliomas, type 1 (PGL1) are caused by mutations in the SDHD gene  and account for up to 50% of cases with hereditary PGL/PCC [8, 9]. However, the frequency of SDHD mutations varies considerably between populations. For example, it is up to 94% in Dutch families . SDHD mutations are mainly found in non-secreting PGLs of the head and neck. In several cases of hereditary PGL/PCC, SDHD mutations were also found in thoracic and pelvic locations, in malignant PGL , and in PCCs (catecholamine-secreting PGLs) [12–14]. Risk for malignant transformation, however, is generally low in PGL1. PGLs caused by mutations in SDHB  are the second most common form and are referred to as PGL4. Frequency of PGL4 is about 20% of PGL/PCC cases. Again, frequency varies among populations and was only found in 6% of Dutch PGL/PCC families  and in 9% of 11 Australian families studied . SDHB mutations are also found in PGL/PCC of the head and neck. In addition, thoracic and abdominal locations are common. Sympathetic paraganglia are more frequently affected, and secreting PGLs (PCC) are more common in PGL4 than in PGL1. Furthermore, the risk for malignant transformation is relatively high in SDHB-PGL/PCC . PGL/PCC caused by mutations in SDHB were also found associated with neuroblastoma . Mutations in SDHC  are rare and make up only about 4% of hereditary PGL/PCC cases. SDHC-related PGLs are referred to as PGL3. They are most commonly non-secreting and benign and occur in the head and neck. As in PGLs caused by SDHD and SDHB mutations [13, 20–23], malignant and secreting tumors have also been found in PGLs caused by SDHC mutations . Mutations in SDHAF2 (SDH5)  are exceedingly rare. Identical mutations, c.232 G > A in exon 2 of SDHAF2, which result in a Gly78Arg change were found in one large Dutch and in one Spanish pedigree . In addition, this same mutation is relatively common in the Netherlands owing to a common founder . Mutations in SDHA have been thought not to occur in PGL and were considered specific for Leigh syndrome, a neurodegenerative disorder. Recently, however, one case with PGL and a mutation in SDHA was detected .
Mechanisms of tumorigenesis in hereditary PGL/PCC
Tumorigenesis is triggered by loss of heterozygosity (LOH), i.e., loss of the wild-type allele in tumors in all five forms of autosomal dominant PGL/PCC . Thus, all hereditary PGL/PCC follow Knudson's classic two-hit model of tumorigenesis. LOH results in severe reduction or loss of the respective components of SDH, i.e., SDHA in one case of hereditary PCC/PGL described so far, SDHB in PGL4, SDHC in PGL3, SDHD in PGL1, and SDHAF2 in PGL2. This reduction/loss of SDH activity interferes with normal function of both the citric acid cycle and the respiratory chain. Succinate and reactive oxygen species (ROS) accumulate [29, 30]. Succinate is an important “oxygen sensor” and stabilizes the hypoxia-dependent subunit of hypoxia inducible factor 1α (HIF1α). This is accomplished by inhibition of HIF-prolyl-hydroxylase (PHD, HPH or EgIN) that is necessary for degradation of HIF1α [31, 32]. As a result, HIF1α is not sufficiently degraded and hypoxia-dependent pathways are activated. Similarly, ROS enables these pathways.
One important hypoxia-inducible gene is vascular endothelial growth factor (VEGF). VEGF induces angiogenesis , a finding consistent with the high degree of vascularization of PGLs. An additional factor contributing to the development of PGL/PCC may include inhibition of apoptosis of neuronal cells. Succinate-mediated inhibition of PHD/HPH/EgIN3 results in loss of the proapoptotic function of this enzyme. Provided inhibition of apoptosis plays a role in tumorigenesis, this inhibition should mainly affect the chief cells (type1 cells) of paraganglia as this cell type is transformed in tumors. Furthermore, the well-established ROS-induced genetic damage could contribute to tumorigenesis. This might occur by damaging DNA repair genes and/or genes that encode proteins involved in regulation of ROS thus accelerating ROS-induced damage [34, 35].
Paternal transmission of PGL1 and PGL2
There is biallelic expression of SDHD in various organs including brain, kidney, and lymphoblastoid cells . To date, no convincing data are available on the expression pattern of SDHD in paraganglia. No findings are presently available for SDHAF2.
The regions of the long arm of chromosome 11 where SDHD (11q23) and SDHAF2 (11q12.2) are located are not genetically imprinted.
The SDHD promoter is neither methylated in the normal adrenal medulla nor in PCCs and breast tumors [36, 37]. Thus, at least, DNA methylation does not appear to be the underlying mechanism causing inactivation of maternally derived SDHD. No findings have been reported on SDHAF2.
Despite exclusive paternal transmission, loss of the maternal allele is a prerequisite for tumor formation. However, if the maternal allele was completely inactivated, tumors should arise even in the absence of LOH. This is clearly not the case.
This hypothesis is not entirely convincing. First, there is no evidence for a paternally imprinted tumor suppressor gene in 11p. Second, this tumor suppressor might also need to be deleted in PGLs 3,4,5. Yet this appears not to be the case, and was excluded in PGL3 [19 and unpublished results]. In PGLs 3,4,5 LOH occurs of the homologous regions of the mutated genes, i.e., SDHC, SDHB, and SDHA, respectively.
In conclusion, the five known forms of hereditary PGL/PCC are caused by germ line mutations in the genes encoding various components of succinate-ubiquinone oxidoreductase and LOH of the respective regions in tumors. The increasing levels of succinate and the resulting cellular hypoxia lead to tumor formation. Given increased occurrence of sporadic PGLs at low oxygen pressure, cellular hypoxia, and thus, similar mechanisms might operate in tumor formation in sporadic as in hereditary PGL/PCC. This knowledge will facilitate the development of conservative treatments for PGL/PCC, which interfere with one or several of the various events leading to and resulting from cellular hypoxia.
I thank Ms Silke Reichmann for preparation of the manuscript.