title: Multiple gastrointestinal stromal and other tumors caused by platelet-derived growth factor receptor alpha gene mutations: a case associated with a germline V561D defect.
abstract: BACKGROUND
  Gastrointestinal stromal tumors (GISTs) may be caused by somatic or germline mutations of the KIT and PDGFRA genes, but most GISTs associated with neuroendocrine tumors (NETs) are not, suggesting that other molecular pathways are implicated in their pathogenesis.
  
  
  OBJECTIVE
  In the course of investigating NETs and GIST genetics, we encountered a patient who had a unique combination of multiple fibrous polyps and lipomas of the small intestine and several gastric GISTs.
  
  
  METHODS
  The study included the clinical description of a unique patient, DNA sequencing of germline and tumor DNA, and comparative genomic hybridization (CGH) and allelic marker analysis of tumor DNA.
  
  
  RESULTS
  The patient was found to carry a germline PDGFRA mutation (V561D) in the heterozygote state; it has only been seen rarely before and only in the somatic state in sporadic GISTs. CGH identified losses of chromosomal regions 1p33-36, 9q12-24, 11q13, and 16q; loss of the 14q region that is commonly lost in NETs and GISTs was shown by DNA marker analysis. These changes are likely to point to secondary and tertiary genetic hits involved in the formation of these rare tumors.
  
  
  CONCLUSIONS
  Multiple GISTs and other tumors may be caused by germline PDGFRA gene mutations; the V561D mutation can occur in the germline state and lead to a syndrome that should not be confused with other genetic conditions associated with a predisposition to NETs and other tumors. A number of chromosomal loci are likely to be involved in the PDGFRA V561D-dependent tumorigenesis, as shown by CGH and other DNA analyses.
authors.affiliation: Department of Genetics, Biology, and Biochemistry, University of Turin, Turin, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pasini
authors.forename: Ludmila
authors.initials: L
authors.lastname: Matyakhina
authors.forename: Thalia
authors.initials: T
authors.lastname: Bei
authors.forename: Michael
authors.initials: M
authors.lastname: Muchow
authors.forename: Sosipatros
authors.initials: S
authors.lastname: Boikos
authors.forename: Barbara
authors.initials: B
authors.lastname: Ferrando
authors.forename: J Aidan
authors.initials: JA
authors.lastname: Carney
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D001224:Aspartic Acid / Q000235:genetics; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D014633:Valine / Q000235:genetics
chemical_list: D001224:Aspartic Acid; D020796:Receptor, Platelet-Derived Growth Factor alpha; D014633:Valine