title: Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors.
abstract: OBJECTIVE
  Activating mutations of the KIT juxtamembrane region are the most common genetic events in gastrointestinal stromal tumors (GISTs) and have been noted as independent prognostic factors. The impact of KIT mutation in other regions, such as the extracellular or kinase domains, is not well-defined and fewer than 30 cases have been published to date.
  
  
  METHODS
  One hundred twenty GISTs, confirmed by KIT immunoreactivity, were evaluated for the presence of KIT exon 9, 11, 13, and 17 mutations. The relation between the presence/type of KIT mutation and clinicopathological factors was analyzed using Fisher's exact test and log-rank test.
  
  
  RESULTS
  Forty-four % of the tumors were located in the stomach, 47% in the small bowel, 6% in the rectum, and 3% in the retroperitoneum. Overall, KIT mutations were detected in 78% of patients as follows: 67% in exon 11, 11% in exon 9, and none in exon 13 or 17. The types of KIT exon 11 mutations were heterogeneous and clustered in the classic "hot spot" at the 5' end of exon 11. Seven % of cases showed internal tandem duplications (ITD) at the 3' end of exon 11, in a region that we designate as a second hot spot for KIT mutations. Interestingly, these cases were associated with: female predominance, stomach location, occurrence in older patients, and favorable outcome. There were significant associations between exon 9 mutations and large tumor size (P < 0.001) and extragastric location (P = 0.02). Ten of these 13 patients with more than 1-year follow-up have developed recurrent disease.
  
  
  CONCLUSIONS
  Most KIT-expressing GISTs show KIT mutations that are preferentially located within the classic hot spot of exon 11. In addition, we found an association between a second hot spot at the 3'end of exon 11, characterized by ITDs, and a subgroup of clinically indolent gastric GISTs in older females. KIT exon 9 mutations seem to define a distinct subset of GISTs, located predominantly in the small bowel and associated with an unfavorable clinical course.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, and Molecular Biology Program, Sloan-Kettering Institute, New York, New York, 10021, USA. antonesc@mskcc.org
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Gunhild
authors.initials: G
authors.lastname: Sommer
authors.forename: Lisa
authors.initials: L
authors.lastname: Sarran
authors.forename: Sylvia J
authors.initials: SJ
authors.lastname: Tschernyavsky
authors.forename: Elyn
authors.initials: E
authors.lastname: Riedel
authors.forename: James M
authors.initials: JM
authors.lastname: Woodruff
authors.forename: Mark
authors.initials: M
authors.lastname: Robson
authors.forename: Robert
authors.initials: R
authors.lastname: Maki
authors.forename: Murray F
authors.initials: MF
authors.lastname: Brennan
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Ronald P
authors.initials: RP
authors.lastname: DeMatteo
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002648:Child; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000556:secondary*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D017354:Point Mutation; D011379:Prognosis; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D016896:Treatment Outcome
chemical_list: D019009:Proto-Oncogene Proteins c-kit