title: C-KIT and PDGFRA zygosity in gastrointestinal stromal tumors: Correlation with tumor site, tumor size, exon, and CD117 immunohistochemistry.
abstract: BACKGROUND
  Gastrointestinal stromal tumors (GISTs) often harbor activating mutations in the receptor tyrosine kinases C-KIT or platelet derived growth factor receptor-alpha (PDGFRA). Gain-of-function mutations in these 2 genes, which result in constitutive signaling, are presumed to be dominant and therefore are usually heterozygous. However, homozygous C-KIT mutations have been reported in GISTs, although at varying frequencies in different subsets.
  
  
  METHODS
  High-resolution amplicon melting curve analysis and direct sequencing were used to determine the frequency of mutation zygosity in a series of 267 GIST cases with known C-KIT (exons 9, 11, 13 and 17) or PDGFRA (exons 12 and 18) mutations. Mutation zygosity was correlated with clinicopathological characteristics including sex, age, tumor size, tumor location, and C-KIT immunohistochemistry.
  
  
  RESULTS
  Forty-two of 267 (15.7%) mutant GISTs were homozygous: 36 in C-KIT exon 11, 1 in C-KIT exon 13, 2 in PDGFRA exon 12, and 3 in PDGFRA exon 18. No correlation was found between mutation zygosity and age, sex, tumor size, or C-KIT expression. Homozygous mutant GISTs from the small intestine were underrepresented (P=0.029) whereas GISTs from metastatic sites such as the liver or pancreas were significantly enriched for mutant homozygosity (P=0.020).
  
  
  CONCLUSIONS
  Zygosity of C-KIT or PDGFRA mutations did not correlate with most clinicopathologic features of GISTs including tumor size in our subset. However, homozygous mutant GISTs were associated with metastatic disease.
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, University of Utah Health Sciences Center, Salt Lake City, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Wallander
authors.forename: Carlynn
authors.initials: C
authors.lastname: Willmore-Payne
authors.forename: Lester J
authors.initials: LJ
authors.lastname: Layfield
mesh_terms: D005091:Exons / Q000235:genetics*; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha