Fast track — ArticlesSDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma
Introduction
Paragangliomas of the head and neck are generally benign tumours that can give rise to substantial morbidity due to compromised function of major blood vessels and cranial nerves of the neck and skull base. Phaeochromocytomas are related closely to these cancers, sharing the neuroectodermal origin of the parasympathetic paragangliomas, but they affect the adrenal medulla and—as sympathetic paragangliomas—intra-abdominal and thoracic paraganglia. Clinical presentation of phaeochromocytomas is usually accompanied by hypertension, sweating, and palpitations due to tumour-derived catecholamine excess. Phaeochromocytomas can be aggressive and metastatic, especially in cases of extra-adrenal localisation.
Germline mutations in genes encoding succinate dehydrogenase—SDHD, SDHC, or SDHB (formerly known as PGL1, PGL3, and PGL4)—are a frequent cause of paragangliomas of the head and neck and phaeochromocytomas, accounting for 30–54% of all cases.1, 2 The major catalytic subunit of the succinate dehydrogenase complex, SDHA, has not been linked to these tumours. Succinate dehydrogenase has a central role in cellular energy metabolism as both a mitochondrial tricarboxylic acid (TCA) cycle enzyme and as the complex II component of the electron transport chain. Since identification of SDHD in 2000,3 the role of TCA enzymes as tumour suppressors has broadened, with mutations of fumarate hydratase reported as the cause of hereditary leiomyomatosis and renal-cell cancer,4 and somatic mutations of isocitrate dehydrogenase genes noted in glioblastoma.5
The SDHAF2 gene (formerly known as PGL2 or SDH5) encodes succinate dehydrogenase complex assembly factor 2 (SDHAF2), a highly evolutionarily conserved cofactor of flavin adenine dinucleotide (FAD).6 SDHAF2 has a role in flavination of SDHA, and correct flavination of this subunit is essential for a fully functional succinate dehydrogenase complex. Loss of SDHAF2 results in loss-of-function of succinate dehydrogenase and a reduction in stability of the enzyme complex, leading to diminished amounts of all subunits.6
In a large Dutch kindred with paragangliomas of the head and neck,6 SDHAF2 carried a missense cDNA mutation, 232G→A (Gly78Arg), in a conserved region, resulting in complete loss of both flavination of SDHA and activity of the succinate dehydrogenase complex. This SDHAF2 gene mutation also showed a striking parent-of-origin expression phenotype, with onset of tumour development only on inheritance via the paternal line. Kindreds containing several family members with head and neck paraganglioma without identified mutations in known susceptibility genes are scarce. However, we have identified a Spanish family in which all three daughters presented with paragangliomas of the head and neck at a young age.
In the first part of this multicentre study, we sought to assess the role of mutations of SDHAF2 in a large cohort of patients with paragangliomas of the head and neck and phaeochromocytomas and to ascertain the proportion of these tumours that can be accounted for by mutation of SDHAF2. In the second part of this study, our objective was to ascertain whether the cancers in the Spanish family are attributable to mutations of SDHAF2. Moreover, by haplotype analysis both of this family and of the Dutch kindred described previously,6 we aimed to assess the level of relatedness between the two families. Here, we use head and neck paraganglioma to describe paragangliomas with locations in the neck—including the carotid body, the vagal body, and jugulotympanic regions—and any other area of the head or neck. We use phaeochromocytoma to describe tumours of the adrenal medulla and of sympathetic paraganglia of the abdomen and thorax.
Section snippets
Patients
We selected patients with paragangliomas of the head and neck and phaeochromocytomas who we had screened previously for mutations of succinate dehydrogenase subunits (SDHD, SDHC, and SDHB). In most cases, full deletion analysis had also been undertaken. Since not all patients were screened exhaustively for all relevant enzyme subunits, a small proportion (2·5%) could have carried a succinate dehydrogenase gene mutation or deletion. This estimate is based on known frequencies of mutations and
Results
To undertake efficient mutation scanning, we brought together patients in whom mutations of the SDHB, SDHC, and SDHD genes had previously been excluded partly or entirely. We analysed 315 individuals for germline mutations of SDHAF2 in genomic DNA, and 200 of these were further analysed for gross gene deletions (123 Spanish and 77 Dutch patients). An additional 100 phaeochromocytoma and 28 head and neck paraganglioma patients from the Netherlands (for whom tumour DNA was available) were
Discussion
More than 290 separate mutations of the paraganglioma-related succinate dehydrogenase genes have been described.20 In analyses of patients with paragangliomas of the head and neck and phaeochromocytomas, 30–54% were reported to carry a mutation.1, 2 Our analysis did not record any germline or somatic mutations, or gross germline deletions, of the SDHAF2 gene in patients with paragangliomas of the head and neck and phaeochromocytomas. Pedigree analysis of a Spanish family with paragangliomas of
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Contributed equally to the paper