title: Prognostic value of KIT mutation type, mitotic activity, and histologic subtype in gastrointestinal stromal tumors.
abstract: OBJECTIVE
  Previous studies have reported clinical correlates for KIT mutations in GISTs, but in most of those studies the KIT mutations were found in less than 50% of the GISTs. The aim of this study was to evaluate the prognostic relevance for KIT mutations in a series of GISTs in which the mutations were evaluated intensively by genomic and cDNA sequencing.
  
  
  METHODS
  A comprehensive clinical and pathologic analysis of 48 patients with GISTs who had snap-frozen tissue was performed. The median tumor size was 10 cm (range, 2 to 30 cm). Median follow-up for disease-free patients was 48 months. KIT genomic and cDNA was sequenced by using nucleic acid templates isolated from frozen tumors.
  
  
  RESULTS
  The overall 5-year recurrence-free survival was 41% +/- 6%. Five-year recurrence-free survival for patients with tumors that had mitotic counts of three mitoses or fewer per 30 high-power fields (HPF), more than three to <or= 15 mitoses per 30 HPF, and more than 15 mitoses per 30 HPF were 89% +/- 7%, 49% +/- 12%, and 16% +/- 6%, respectively (P =.0001). The 32 patients with spindle-cell histology had a 49% +/- 7% 5-year recurrence-free survival; in contrast, the 16 patients with epithelioid or mixed histology had a 23% +/- 11% 5-year recurrence-free survival (P =.01). Five-year recurrence-free survival for patients with tumors less than 5 cm, 5 to 10 cm, and more than 10 cm were 82% +/- 12%, 45% +/- 9%, and 27% +/- 8%, respectively (P =.03). Prognostic associations were found with particular KIT mutation types, and patients with missense exon 11 mutations had a 5-year recurrence-free survival of 89% +/- 11% compared with 40% +/- 8% for GISTs with other mutation types (P =.03). The independent predictors for disease-free survival were the presence of deletion/insertion exon 11 mutations (hazard ratio [HR] = 4; P =.006), more than 15 mitoses per 30 HPF (HR = 18; P =.0001), mixed histology (HR = 21; P =.0001), and male sex (HR = 3; P =.05).
  
  
  CONCLUSIONS
  In this series of KIT-expressing GISTs, tumor mitotic activity and histologic subtype were the most important prognostic features. The majority of GISTs contain KIT-activating mutations with the type/location of mutation serving as an independent predictor for disease-free survival. These results suggest that KIT mutation and activation are important in GIST pathogenesis and also may provide important prognostic information.
authors.affiliation: Department of Pathology and Surgery, Brigham and Women's Hospital, Boston, MA, USA. singers@mskcc.org
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.forename: Marcia L
authors.initials: ML
authors.lastname: Lux
authors.forename: Chang-Jie
authors.initials: CJ
authors.lastname: Chen
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D004273:DNA, Neoplasm; D018572:Disease-Free Survival; D005091:Exons; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D015996:Survival Rate
chemical_list: D018076:DNA, Complementary; D004273:DNA, Neoplasm; D019009:Proto-Oncogene Proteins c-kit