title: High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Section of Medical Neuroendocrinology, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institute of Health, Bethesda, Maryland 20892-1109, USA.
authors.forename: Frederieke M
authors.initials: FM
authors.lastname: Brouwers
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Tao
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kant
authors.forename: Karen T
authors.initials: KT
authors.lastname: Adams
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
mesh_terms: D000008:Abdominal Neoplasms / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002395:Catecholamines / Q000378:metabolism*; D002648:Child; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism*; D010236:Paraganglioma, Extra-Adrenal / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: D002395:Catecholamines; D007506:Iron-Sulfur Proteins; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase