title: SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas.
abstract: BACKGROUND
  Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA.
  
  
  OBJECTIVE
  In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations.
  
  
  METHODS
  This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France).
  
  
  METHODS
  We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA.
  
  
  RESULTS
  Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C → T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C → T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations.
  
  
  CONCLUSIONS
  Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas.
authors.affiliation: Department of Pathology, Erasmus MC-University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands. e.korpershoek.1@erasmusmc.nl
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
authors.forename: José
authors.initials: J
authors.lastname: Gaal
authors.forename: Nelly
authors.initials: N
authors.lastname: Burnichon
authors.forename: Bram
authors.initials: B
authors.lastname: van Gessel
authors.forename: Lindsey
authors.initials: L
authors.lastname: Oudijk
authors.forename: Cécile
authors.initials: C
authors.lastname: Badoual
authors.forename: Noémie
authors.initials: N
authors.lastname: Gadessaud
authors.forename: Annabelle
authors.initials: A
authors.lastname: Venisse
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bayley
authors.forename: Marieke F
authors.initials: MF
authors.lastname: van Dooren
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Plouin
authors.forename: Francien H
authors.initials: FH
authors.lastname: van Nederveen
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D004252:DNA Mutational Analysis; D042963:Electron Transport Complex II / Q000235:genetics* / Q000378:metabolism; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism
chemical_list: D042963:Electron Transport Complex II; C511268:SDHA protein, human