title: Differential expression of KIT/PDGFRA mutant isoforms in epithelioid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site.
abstract: Gastrointestinal stromal tumors (GISTs) form a distinctive group of mesenchymal neoplasms, showing differentiation towards the interstitial cells of Cajal. Morphologically, GISTs vary from cellular spindle cell tumors to epithelioid or mixed, epithelioid and spindle cell variants. The genotypic features underlying the morphologic differences of GISTs with vs without epithelioid components are not well defined. Acquisition of activating mutations in KIT and PDGFRA has been reported as alternative oncogenic events in the pathogenesis of GISTs. In this study, a comprehensive KIT and PDGFRA mutational analysis was performed in a group of 28 epithelioid/mixed type tumors, in order to explore whether a specific KIT/PDGFRA mutational status segregates these neoplasms from spindle cell variant GISTs. All GISTs were primary neoplasms, 16 (57.1%) originated from the stomach and 12 (42.8%) from other locations. Histomorphologically, 14 GISTs showed an epithelioid and 14 a mixed cell type pattern. Mutational analysis included KIT exons 9, 11, 13, and 17, and PDGFRA exons 12 and 18 prescreening by denaturing high-performance liquid chromatography, followed by direct sequencing. Activating mutations of KIT were found in 14 (50%) GISTs, the majority being within exon 11 (n=11; 39.2%), and the other comprised exon 9 AY 502-503 duplications (n=2; 7.2%) and exon 17 Lys --> Aln822 missense mutations (n=1; 3.6%). Most of the KIT mutant tumors (n=11; 78.6%) originated from nongastric sites. Seven (25.0%) GISTs with no detectable KIT mutations demonstrated PDGFRA mutant isoforms, carrying either D842 V mutations (n=5) or exon 18 deletions (n=2). All GISTs harboring PDGFRA mutant isoforms originated from the stomach. In seven tumors, no detectable mutations were found; all but one of nonmutant tumors initiated from the stomach and exhibited an epithelioid morphology. These findings indicate that the mutational status of epithelioid/mixed GISTs associates with the anatomical site of the tumor.
authors.affiliation: Laboratory for Cytogenetics and Molecular Genetics of Human Malignancies, Department for Human Genetics, Catholic University of Leuven, Belgium.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Wasag
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Patrick
authors.initials: P
authors.lastname: Pauwels
authors.forename: Michel
authors.initials: M
authors.lastname: Stul
authors.forename: Hilde
authors.initials: H
authors.lastname: Vranckx
authors.forename: Allan Van
authors.initials: AV
authors.lastname: Oosterom
authors.forename: Anne
authors.initials: A
authors.lastname: Hagemeijer
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000473:pathology*; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D020033:Protein Isoforms / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D004273:DNA, Neoplasm; D020033:Protein Isoforms; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha