title: SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors.
abstract: BACKGROUND
  A subset of KIT/PDGFRA wild-type gastrointestinal stromal tumors (WT GIST) have been associated with alteration of the succinate dehydrogenase (SDH) complex II function. A recent report identified four non-syndromic, KIT/PDGFRA WT GIST harboring compound heterozygous or homozygous mutations in SDHA encoding the main subunit of the SDH complex II.
  
  
  METHODS
  Next generation sequencing was applied on five pediatric and one young adult WT GIST, by whole exome capture and SOLiD 3-plus system sequencing. The putative mutations were first confirmed by Sanger sequencing and then screened on a larger panel of 11 pediatric and young adult WT GIST, including 5 in the context of Carney triad.
  
  
  RESULTS
  A germline p.Arg31X nonsense SDHA mutation was identified in one of the six cases tested by SOLiD platform. An additional p.D38V missense mutation in SDHA exon 2 was identified by Sanger sequencing in the extended KIT/PDGFRA WT GIST patients cohort. Western blotting showed loss of SDHA expression in the two cases harboring SDHA mutations, while expression being retained in the other WT GIST tumors. Results were further confirmed by immunohistochemistry for both SDHA and SDHB, which showed a concurrent loss of expression of both proteins in SDHA-mutant lesions, while the remaining WT tumors showed only loss of SDHB expression.
  
  
  CONCLUSIONS
  Germline and/or somatic aberrations of SDHA occur in a small subset of KIT/PDGFRA WT GISTs, outside the Carney's triad and are associated with loss of both SDHA and SDHB protein expression. Mutations of the SDH complex II are more particularly associated with KIT/PDGFRA WT GIST occurring in young adults. Although pediatric GIST consistently display alterations of SDHB protein expression, further molecular studies are needed to identify the crucial genes involved in their tumorigenesis.
authors.affiliation: Departments of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.forename: Yun-Shao
authors.initials: YS
authors.lastname: Sung
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Ronald P
authors.initials: RP
authors.lastname: DeMatteo
authors.forename: Michael P
authors.initials: MP
authors.lastname: LaQuaglia
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
authors.forename: Nicholas
authors.initials: N
authors.lastname: Socci
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D042963:Electron Transport Complex II / Q000235:genetics*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D017422:Sequence Analysis, DNA; D013385:Succinate Dehydrogenase / Q000235:genetics
chemical_list: D042963:Electron Transport Complex II; C511268:SDHA protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha