Gastrointestinal Stromal Tumor (GIST)
Molecular Genetic Studies
- Frequency of KIT mutations
| KIT |
|
exon 9 |
18% |
exon 11 |
67% |
exon 13 |
2% |
exon 17 |
2% |
| PDGFRA |
|
exon 12 |
1% |
exon 18 |
4% |
- Screening for kinase mutations in suspectied GISTs can be clinically useful
- Molecular confirmation of GIST
- Clinical response to treatment with small molecular inhibitor Gleevec is predicted by mutation status
- KIT exon 11 mutant GIST are sensitive to low doses
- No increased response from higher dose
- KIT exon 9 mutations predict drug dose sensitivity
- High doses are more effective than low
- KIT immunohistochemistry negative cases have a gain of function KIT mutation
- Usually exon 11
- Responsive to anti-KIT therapy
- GIST with PDGFRa exon 18 D842 V mutations are resistant to Gleevec
- Secondary mutations may follow treatment with small molecule inhibitors
- Typically clustered in KIT ATP binding pocket and kinase catalytic regions
- Drugs effective against such mutations are in development
- Other tumors with KIT mutations
- Acute myelogenous leukemia
- Mastocytosis
- Myeloproliferative disorders
- Primary mediastinal germ cell tumor
- Seminoma
- For more reading:
- Heinrich 2003, 2008
- Corless 2005
