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Updated: Jul 18, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)
Jerzy Lasota1, Markku Miettinen
1Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA. lasota@afip.osd.mil
Abstract:
Mutually exclusive KIT and PDGFRA mutations are central events in GIST pathogenesis, and their understanding is becoming increasingly important, because specific treatment targeting oncogenic KIT and PDGFRA activation (especially imatinib mesylate) has become available. KIT mutations in GIST are clustered in four exons. Most common are exon 11 (juxtamembrane domain) mutations that include deletions, point mutations (affecting a few codons), and duplications (mostly in the 3' region). The latter mutations most often occur in gastric GISTs. Among gastric GISTs, tumors with deletions are more aggressive than those with point mutations; this does not seem to hold true in small intestinal GISTs. Exon 9 mutations (5-10%) usually are 2-codon 502-503 duplications, and these occur predominantly in intestinal versus gastric GISTs. Lesser imatinib sensitivity of these tumors has been noted. Kinase domain mutations are very rare; GISTs with such mutations are variably sensitive to imatinib. PDGFRA mutations usually occur in gastric GISTs, especially in the epithelioid variants; their overall frequency is approximately 30% to 40% of KIT mutation negative GISTs. Most common is exon 18 mutation leading Asp842Val at the protein level. This mutation causes imatinib resistance. Exon 12 and 14 mutations are rare. Most mutations are somatic (in tumor tissue only), but patients with familial GIST syndrome have consitutitonal KIT/PDGFRA mutations; >10 families have been reported worldwide with mutations generally similar to those in sporadic GISTs. GISTs in neurofibromatosis 1 patients, children, and Carney triad seem to lack GIST-specific KIT and PDGFRA mutations and may have a different disease mechanism. Secondary mutations usually occur in KIT kinase domains in patients after imatinib treatment resulting in resistance to this drug. Mutation genotyping is a tool in GIST diagnosis and in assessment of sensitivity to kinase inhibitors. This is a US government work. There are no restrictions on its use.
Insights
Understanding KIT and PDGFRA mutations in gastrointestinal stromal tumors (GIST) is crucial for targeted therapies like imatinib. Mutation type and location influence GIST behavior and treatment response.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastrointestinal stromal tumors (GIST) are primarily driven by mutations in KIT or PDGFRA genes.
- Targeted therapies, such as imatinib mesylate, have revolutionized GIST treatment by inhibiting oncogenic KIT and PDGFRA.
- Understanding the spectrum and implications of these mutations is vital for personalized GIST management.
Purpose of the Study:
- To review the central role of KIT and PDGFRA mutations in GIST pathogenesis.
- To detail the common mutation sites within KIT (exons 11 and 9) and PDGFRA (exon 18).
- To discuss the clinical significance of these mutations regarding GIST behavior and imatinib sensitivity.
Main Methods:
- Review of existing literature on GIST genetics and targeted therapy.
- Analysis of mutation patterns in KIT and PDGFRA genes.
- Correlation of mutation status with clinical presentation and treatment outcomes.
Main Results:
- KIT mutations are common, with exon 11 mutations prevalent in gastric GISTs and exon 9 duplications in intestinal GISTs, impacting imatinib sensitivity.
- PDGFRA mutations, particularly Asp842Val in exon 18, are found in KIT-negative GISTs and confer imatinib resistance.
- Familial GIST syndromes involve constitutional KIT/PDGFRA mutations, while pediatric GISTs and those in specific syndromes may have different genetic underpinnings.
Conclusions:
- Mutation genotyping is essential for GIST diagnosis and predicting response to kinase inhibitors.
- Specific KIT and PDGFRA mutations dictate therapeutic strategies and prognosis in GIST patients.
- Further research into non-canonical GIST mutations may elucidate alternative therapeutic targets.
