Mutation of SDHB is a Cause of Hypoxia-Related High-Altitude Paraganglioma

Abstract

Purpose: Paragangliomas of the head and neck are neuroendocrine tumors and are associated with germ line mutations of the tricarboxylic acid cycle-related genes SDHB, SDHC, SDHD, and SDHAF2. Hypoxia is important in most solid tumors, and was directly implicated in tumorigenesis over 40 years ago when it was shown that dwelling at high altitudes increases the incidence of carotid body hyperplasia and paragangliomas. Although recent research has now elucidated several pathways of hypoxia in paragangliomas, nothing is currently known of the genetics or of gene-environment interactions in highaltitude paraganglioma. We postulated that SDH mutations might play a role in these tumors.Experimental Design: Patients from a Mexican family, originating and resident in Guadalajara, were tested for mutations of SDHD, and subsequently, for mutations of SDHB followed by immunohistochemical confirmation of SDHB loss.Results: Two patients, born and resident at altitudes of between 1,560 and 2,240 m, were found to have head and neck paragangliomas, including a remarkably aggressive recurrent tumor. Mutation analysis identified a pathogenic missense mutation in exon 7 of SDHB, c.689G>A, p.Arg230His, and loss of the SDHB protein was confirmed by immunohistochemistry.Conclusions: This is the first report of a SDH gene mutation in paraganglioma at high altitude. A rapidly recurrent head and neck paraganglioma is a very rare finding in an SDH mutation carrier, suggesting a gene-environment interaction. Neither patient showed evidence of sympathetic paraganglioma. Paragangliomas of the head and neck (HN-PGL; also referred to as chemodectomas) are rare, mostly benign tumors of the parasympathetic nervous system. They occur most commonly in the carotid body, the main peripheral sensor of physiologic hypoxia (low oxygen levels). Paragangliomas of the sympathetic nervous system (sPGL) arise in the adrenal medulla or in the extra-adrenal paraganglia of the thorax and abdomen, and are often referred to as pheochromocytomas or extra-adrenal paragangliomas.A genetic basis for HN-PGL was established with the identification by Baysal et al. (1) of germ line mutations in the succinate dehydrogenase, subunit D gene (SDHD). Other subunits of SDH and related proteins were subsequently shown to be involved in HN-PGL and sPGL (2-4). These genes encode subunits or associated proteins of the succinate dehydrogenase complex, which plays a central role in energy metabolism as both an enzyme of tricarboxylic acid cycle and as complex II of the mitochondrial respiratory chain, involved in oxidative phosphorylation.In recent years, there has been a revival of interest in metabolic adaptations of solid tumors, specifically the very high rate of glycolysis and decline in tricarboxylic acid cycle activity, often referred to as the "Warburg effect" (5, 6). The Warburg effect is fundamental to a broad range of tumors and is now the basis for the widely used technique of 18 F-fluorodeoxyglucose positron emission tomography tumor imaging (7). The discovery ...

Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations: Further Cases and Implications for Genetic Counselling

“…Information on genetic testing of other family members was not available. Both mutations have been reported previously; c.143A>T (p.Asp48Val) has been found homozygous and compound heterozygous in patients with leukodystrophy and complex II deficiency (Alston et al 2012;Helman et al 2015), whereas the c.689G>A (p.Arg230His) mutation has been reported in heterozygous form in two patients with apparently sporadic paraganglioma/pheochromocytoma (Amar et al 2005), in a family with paraganglioma/ pheochromocytoma and renal cell cancer (Ricketts et al 2012), as well as in patients with head and neck paraganglioma (Cerecer-Gil et al 2010;Peterson et al 2014). …”

Hypoxia Pathway Mutations in Pheochromocytomas and Paragangliomas

“…Noteworthy, carotid body HNPGL occur 10 times more frequently in populations living in high altitudes (low oxygen levels), than in those living at sea level; this is particularly evident when comparing Peruvians born and living in the Andes with those living at sea level [Jyung et al, 2000;CerecerGil et al, 2010]. In this context, gene-environment interactions, involving mutations of the SDHx gene family and hypoxic environmental stimuli, may also be relevant for HNPGL development [Cerecer-Gil et al, 2010]. An outstanding epidemiologic aspect of carotid body HNPGL is their female preponderance, particularly in high altitude context.…”

“…An outstanding epidemiologic aspect of carotid body HNPGL is their female preponderance, particularly in high altitude context. This may be explained by an estrogenic influence in tumor development, a reduced pulmonary capacity in females, or other factors such as periodic blood loss through menstruation [Jyung et al, 2000;Cerecer-Gil et al, 2010].…”

15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations

“…The paraganglioma tumor formation may thus follow chronic hypoxic stimulation of the CB oxygensensing (chief) cells, either by environmental hypoxia or by SDH mutations that inhibit oxygen sensing. The hypothesis that chronic (pseudo)hypoxic stimulation may lead to hereditary paragangliomas is also supported by evidence that links increased altitudes to increased severity of SDH-mutated paraganglioma tumors (Astrom et al 2003, Cerecer-Gil et al 2010.…”