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High Frequency of SDHB Germline Mutations in Patients with Malignant Catecholamine-Producing Paragangliomas: Implications for Genetic Testing

Section on Medical Neuroendocrinology, Reproductive Biology, and Medicine Branch (F.M.B., J.J.T., K.T.A., K.P.), National Institute of Child Health and Human Development; Clinical Neurocardiology Section (G.E.), National Institute of Neurological Disorders and Stroke; and Urologic Oncology Branch (W.M.L.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1109; and Division of Molecular Diagnostics (J.A.K.), Departments of Pathology and Human Genetics, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213

Address all correspondence and requests for reprints to: Karel Pacak, M.D., Ph.D., D.Sc.., Building 10, CRC, Room 1E-1-3140, 10 Center Drive, MSC-1109, Bethesda, Maryland 20892-1109. E-mail: karel{at}mail.nih.gov.

Context: Adrenal and extraadrenal paragangliomas are tumors of chromaffin cells that are usually benign but that may also develop into malignant disease. Mutations of the gene for succinate dehydrogenase subunit B (SDHB) are associated with a high risk of malignancy, but establishing the precise contribution requires relatively large numbers of patients with well-defined malignancy.

Objective: We assessed the prevalence of SDHB mutations in a series of patients with malignant paraganglioma.

Design: SDHB mutation testing was carried out in 44 consecutive patients with malignant paraganglioma. Clinical characteristics of patients with malignant disease due to SDHB mutations were compared with those without mutations.

Results: Pathogenic SDHB mutations were found in 13 of the 44 patients (30%). Close to one third of patients had metastases originating from an adrenal primary tumor, compared with a little over two thirds from an extraadrenal tumor. Among the latter patients, the frequency of SDHB mutations was 48%.

Conclusion: This study establishes that missense, nonsense, frameshift, and splice site mutations of the SDHB gene are associated with about half of all malignancies originating from extraadrenal paragangliomas. The high frequency of SDHB germline mutations among patients with malignant disease, particularly when originating from an extraadrenal paraganglioma, may justify a high priority for SDHB germline mutation testing in these patients.

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