title: PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor.
abstract: 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.
authors.affiliation: Department of Medicine, Institut Gustave Roussy, Villejuif, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Chompret
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.forename: Michel
authors.initials: M
authors.lastname: Barrois
authors.forename: Philippe
authors.initials: P
authors.lastname: Terrier
authors.forename: Philippe
authors.initials: P
authors.lastname: Dahan
authors.forename: Thomas
authors.initials: T
authors.lastname: Tursz
authors.forename: Gilbert M
authors.initials: GM
authors.lastname: Lenoir
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-De Paillerets
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
chemical_list: D020796:Receptor, Platelet-Derived Growth Factor alpha