[c-kit and PDGFRA mutations in 60 cases of gastrointestinal stromal tumors (GISTs)].
OBJECTIVE
To explore the status of activating mutations of c-kit and PDGFRA in GIST of Chinese patients.


METHODS
Sixty GISTs, confirmed by immunoreactivity of CD117, CD34, SMA, S-100 and Desmin, were evaluated for the presence of c-kit exons 9, 11, 13 and 17 mutations, and PDGFRA exons 12 and 18 mutations. The PCR products were sequenced directly for mutations, using DNA extracted from paraffin-embedded tissue.


RESULTS
53% of the tumors were located in the stomach, 22% in the small bowel, 8% in the colo rectum, 2% in the esophagus and 15% in the extragastrointestinal tract. Immunohistochemical demonstrations of c-kit (CD117) were seen in 90% cases. Overall, c-kit mutations were detected in 63.3% of patients as follows: 58.3% in exon 11, 3.3% in exon 9, 1.7% in exon 13 and none in exon 17. The types of c-kit exon 11 mutations were mostly heterogeneous and clustered in the classic "hot spot" at the 5' end of exon 11, 42.9% being point mutation and in-frame deletion at Codon 557-560. 14.3% of cases showed internal tandem duplications (ITD) at the 3' end of exon 11 in a region of a second hot spot for c-kit mutations. Interestingly, these cases were associated with female predominance, stomach location and occurrence in older patients. The present study failed to identify a significant association between c-kit mutation status and risk of aggressive behavior in GISTs. Exon 9 mutations consisted of ITP of six nucleotides encoding Ala-Tyr. A new point mutation of L641P was revealed in exon 13. PDGFRA mutations were found in 5% of all the 60 cases with none of the positive cases expressed detectable KIT protein. The type of mutation was the commonest point mutation of D842V of exon 18.


CONCLUSIONS
Most KIT expressing GIST show c-kit mutations that are preferentially located within the classic hot spot of exon 11. A second hot spot -ITD at the 3' end of exon 11 seems to associate with a subgroup of gastric GISTs in older females. c-kit exons 9, 13 and 17 mutations are rare events in GIST of China. PDGFRA oncogenic mutations are more likely seen in KIT-negative GISTs arising in the peritoneal surface and have an unfavorable clinical course.
He
Hui-ying
HY
Department of Pathology, Peking University School of Basic Medical Scienes, Beijng 100083, China.
Xiang
Yi-ning
YN
Li
Yan
Y
Zhong
Hao-hao
HH
Wu
Bing-quan
BQ
Zheng
Jie
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001483:Base Sequence; D005091:Exons / Q000235:genetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D017154:Stromal Cells
D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha