PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor

Gastroenterology. 2004 Jan;126(1):318-21. doi: 10.1053/j.gastro.2003.10.079.


Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder associated with KIT germline mutations. In sporadic forms of the disease, somatic mutations target either KIT or PDGFRA genes. In a kindred in which 5 individuals had GIST, no germline mutation in KIT coding sequence has been detected. We hypothesized that the PDGFRA gene could be a predisposing gene in familial GIST. We sequenced PDGFRA exons 12 and 18 because several somatic mutations were identified within this region. We detected a germline PDGFRA missense mutation, 2675G > T, resulting in a tyrosine substitution for the highly conserved aspartic acid at codon 846. This mutation showed perfect cosegregation with the GIST phenotype among the 7 family members tested. Interestingly, PDGFRA Asp846 is homologous to codon 820, which is located in the KIT tyrosine kinase II domain. In a previous study, a KIT germline Asp820Tyr mutation was detected in a Japanese kindred in which 6 individuals had GIST. Transfection of a KIT820Tyr complementary DNA in nude mice was found to be tumorigenic confirming the oncogenic potential of this mutation. The present study shows that PDGFRA is a second familial GIST predisposing gene. These results indicate a further example of involvement of structurally related genes in familial cancer syndromes.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Amino Acid Sequence / genetics
  • Base Sequence / genetics
  • Female
  • Gastrointestinal Neoplasms / genetics*
  • Genetic Predisposition to Disease / genetics
  • Germ-Line Mutation / genetics*
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Pedigree
  • Receptor, Platelet-Derived Growth Factor alpha / genetics*


  • Receptor, Platelet-Derived Growth Factor alpha