Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis.
OBJECTIVE
Gain-of-function mutations in the KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene are important events in gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up.


METHODS
Genomic DNA from 177 GIST patients was analyzed for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing.


RESULTS
KIT exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT) KIT and PDGFRA were detected in 63; KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST </=1 cm had mutations in 73% and 33%, respectively. KIT exon 11 deletions were significantly associated with a higher proportion of high risk or overtly malignant groups compared with WT GIST. KIT exon 11 deletions adversely affected outcome. KIT exon 11 duplications and exon 9 mutations were found exclusively in gastric and small intestinal GIST, respectively.


CONCLUSIONS
KIT exon 11 deletion is an independent adverse prognostic factor in patients with GIST.
Andersson
Johanna
J
Department of Pathology at the Sahlgrenska Academy, Lundberg Laboratory for Cancer Research, Göteborg University, Göteborg, Sweden.
Bümming
Per
P
Meis-Kindblom
Jeanne M
JM
Sihto
Harri
H
Nupponen
Nina
N
Joensuu
Heikki
H
Odén
Anders
A
Gustavsson
Bengt
B
Kindblom
Lars-Gunnar
LG
Nilsson
Bengt
B
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011336:Probability; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D012189:Retrospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D015996:Survival Rate
D014408:Biomarkers, Tumor; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha