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Recent Advances in the Genetics of SDH-Related Paraganglioma and Pheochromocytoma

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Recent Advances in the Genetics of SDH-Related Paraganglioma and Pheochromocytoma View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by DSpace at VU Familial Cancer (2011) 10:355–363 DOI 10.1007/s10689-010-9402-1 Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma Erik F. Hensen • Jean-Pierre Bayley Published online: 17 November 2010 Ó The Author(s) 2010. This article is published with open access at Springerlink.com Abstract The last 10 years have seen enormous progress lack of expression of SDHD and SDHAF2 mutations when in the field of paraganglioma and pheochromocytoma inherited via the maternal line. Little is still known of the genetics. The identification of the first gene related to par- origins and causes of truly sporadic tumors, and the role of aganglioma, SDHD, encoding a subunit of mitochondrial oxygen in the relationships between high-altitude, familial succinate dehydrogenase (SDH), was quickly followed by and truly sporadic paragangliomas remains to be elucidated. the identification of mutations in SDHC and SDHB. Very recently several new SDH-related genes have been dis- Keywords Paraganglioma Á Pheochromocytoma Á covered. The SDHAF2 gene encodes an SDH co-factor SDHA Á SDHAF1 Á SDHAF2 Á SDHB Á SDHC Á SDHD Á related to the function of the SDHA subunit, and is currently TMEM127 exclusively associated with head and neck paragangliomas. SDHA itself has now also been identified as a paragangli- oma gene, with the recent identification of the first mutation Introduction in a patient with extra-adrenal paraganglioma. Another SDH-related co-factor, SDHAF1, is not currently known to Prior to the year 2000, knowledge of the genetics of para- be a tumor suppressor, but may shed some light on the ganglioma and pheochromocytoma was confined to mutations mechanisms of tumorigenesis. An entirely novel gene of the VHL, RET and NF1 genes. The identification of muta- associated with adrenal pheochromocytoma, TMEM127, tions in the succinate dehydrogenase subunit D gene (SDHD) suggests that other new paraganglioma susceptibility genes in patients with head and neck paraganglioma [1] was there- may await discovery. In addition to these recent discoveries, fore a major breakthrough. The association of paraganglioma new techniques related to mutation analysis, including with mutations in SDHD, and later with mutations in other genetic analysis algorithms, SDHB immunohistochemistry, SDH subunits, has helped elucidate both the role of the and deletion analysis by MLPA have improved the effi- mitochondrial SDH complex and intermediary metabolism in ciency and accuracy of genetic analysis. However, many tumorigenesis. The subsequent discovery of SDH mutations intriguing questions remain, such as the striking differences in patients with pheochromocytomas and extra-adrenal para- in the clinical phenotype of genes that encode proteins with gangliomas [2] led to a recognition that paragangliomas and an apparently very close functional relationship, and the pheochromocytomas share not only similar cellular origins, but can also have a comparable genetic basis. Paragangliomas of the head and neck are generally E. F. Hensen benign tumors that arise in the paraganglion tissue associ- Department of Otolaryngology and Head- and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands ated with the autonomic nervous system. Paragangliomas most frequently arise in the head and neck region, as carotid J.-P. Bayley (&) body tumors in the carotid bifurcation (approximately 80%). Department of Human Genetics, Leiden University Medical Other frequently seen locations within the head and neck Centre, PZ S-04, P.O. Box 9600, 2300, RC, Leiden, The Netherlands region are along the jugular bulb or tympanic nerve (17.5%), e-mail: [email protected] or the paraganglia along the vagal nerve (4.5%) [3]. 123 356 E. F. Hensen, J.-P. Bayley Pheochromocytomas and extra-adrenal paragangliomas within their spectrum include the multiple endocrine neopla- are tumors associated with the sympathetic nervous system, sia syndromes, MEN2A and MEN2B, caused by mutations are commonly described as sympathetic paragangliomas of the RET (Rearranged in Transfection) proto-oncogene, (sPGLs), and show a close embryological and physiologi- subtypes of von Hippel-Lindau (VHL) disease, caused by cal relationship to head and neck paragangliomas. They are mutations of the VHL tumor suppressor gene, and neurofi- most commonly derived from the chromaffin cells of the bromatosis type 1 (NF1) resulting from mutations of the NF1 adrenal medulla (pheochromocytoma), but approximately tumor suppressor gene [7]. These syndromes account for 10–20% occur elsewhere in the abdomen [4], but can occur around 17% of cases [6] but are rarely associated with head from the neck to the pelvic floor in any of the sympathetic and neck or extra-adrenal paragangliomas. paraganglia. Extra-adrenal sympathetic paragangliomas More recently, mutations in genes associated with the show a greater degree of malignancy than either pheo- mitochondrial succinate dehydrogenase (SDH) complex chromocytomas or head and neck paragangliomas [5]. (SDHA, SDHB, SDHC, SDHD and SDHAF2) have been Here we discuss recent advances in the understanding of shown to cause head and neck paragangliomas, extra-adre- the genetic basis of both head and neck paragangliomas nal paragangliomas, and pheochromocytomas (Table 1)[1, and pheochromocytomas, and further developments rele- 2, 8–11]. These genes account for the remaining 15% of vant to the genetic diagnosis of these tumors. cases [6]. All of these genes are tumor suppressors, showing loss of heterozygosity (LOH), the loss of the normal allele in the tumor, in conjunction with the germline mutation. This Genetics results in loss of a protein subunit, which in turn destabilizes the SDH complex and abolishes its enzymatic activity [12]. Presently, causative gene mutations can be identified in Succinate dehydrogenase is an enzyme of the mito- around 32% of paraganglioma-pheochromocytomas [6]. chondrial tricarboxylic acid cycle, and also plays an Hereditary tumor syndromes which have pheochromocytoma important role as the complex II component of the electron Table 1 Summary of genes, known protein functions and related syndromes Gene Locus Protein function Gene mechanism No. of Syndrome Primary locations unique mutationsa SDHD 11q23 One of the two transmembrane Autosomal 110 Hereditary Head and neck; subunits of Complex II of the dominant with paraganglioma/ parasympathetic trunk respiratory chain LOH ? pheochromocytoma imprinting SDHB 1p36.1- The iron-sulfur protein catalytic Autosomal 175 Hereditary Abdominal/thoracic p35 subunit of Complex II dominant with paraganglioma/ paraganglia, adrenal; LOH pheochromocytoma sympathetic trunk SDHC 1q23.3 One of the two transmembrane Autosomal 34 Hereditary Head and neck; subunits of Complex II of the dominant with paraganglioma/ parasympathetic trunk respiratory chain LOH pheochromocytoma SDHAF2 11q12.2 Mitochondrial assembly factor Autosomal 1 Hereditary Head and neck; for Complex II—interacts dominant with paraganglioma/ parasympathetic trunk directly with SDHA LOH ? pheochromocytoma imprinting SDHA 5p15 The flavoprotein catalytic subunit Autosomal 1 Hereditary Abdominal paraganglia, of Complex II dominant with paraganglioma/ sympathetic trunk LOH pheochromocytoma SDHA 5p15 The flavoprotein catalytic subunit Autosomal 7 Mitochondrial Systemic of Complex II recessive encephalopathy/ Leigh Syndrome SDHAF1 19q13.12 Mitochondrial assembly factor Autosomal 2 Infantile Systemic for Complex II. Interacts recessive leukoencephalopathy directly with SDHB? TMEM127 2q11.2 Transmembrane protein involved Autosomal 8 Hereditary Adrenal; sympathetic in protein trafficking dominant with pheochromocytoma trunk LOH a Number of mutations derived from the literature or the TCAC gene mutation database [34] 123 Recent advances in the genetics 357 transport chain, contributing to the generation of ATP by syndrome in many parts of the world, despite a relatively oxidative phosphorylation. These combined roles place low penetrance of SDHB mutations of 25–40% [24–26]. SDH at the center of two of the essential energy producing Due to their lower penetrance, SDHB mutations are often processes of the cell. SDHA is a flavoprotein, and SDHB, found in apparently sporadic patients [27]. SDHB mutations an iron-sulfur protein, and together they form the main primarily predispose to sPGLs, and around 20% of SDHB catalytic domain, while SDHC and SDHD are the mem- mutation carriers will develop metastatic disease [5, 6]. brane-anchoring subunits of SDH and play a role in passing electrons through the electron transport chain. Despite the fact that SDH proteins are all components of the same SDHC protein complex, mutations lead to clear differences in clinical phenotype. The molecular basis for this clinical SDHC was the second SDH subunit gene identified as a divergence is not currently known. cause of paragangliomas [11]. Paragangliomas due to mutations in SDHC are much rarer than SDHB- and SDHD- related paragangliomas, accounting for less than 1% of all SDHD patients in a recent study [6]. SDHC mutations result pri- marily in head and neck paragangliomas, but have also Researchers in the Netherlands were the first to success- been identified in patients with sympathetic paraganglio- fully tackle the genetics of head and neck paraganglioma mas [28, 29]. [13–18] and they were greatly assisted by the unusual social and demographic history of the country. Until rela- tively recently, the Netherlands
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