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Updated: Aug 22, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Biology of gastrointestinal stromal tumors
Christopher L Corless1, Jonathan A Fletcher, Michael C Heinrich
1Oregon Health & Science University Cancer Institute, Department of Pathology, Portland, OR, USA.
Abstract:
Once a poorly defined pathologic oddity, in recent years, gastrointestinal stromal tumor (GIST) has emerged as a distinct oncogenetic entity that is now center stage in clinical trials of kinase-targeted therapies. This review charts the rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis. Approximately 80% to 85% of GISTs harbor activating mutations of the KIT tyrosine kinase. In a series of 322 GISTs (including 140 previously published cases) studied by the authors in detail, mutations in the KIT gene occurred with decreasing frequency in exons 11 (66.1%), 9 (13%), 13 (1.2%), and 17 (0.6%). In the same series, a subset of tumors had mutations in the KIT-related kinase gene PDGF receptor alpha (PDGFRA), which occurred in either exon 18 (5.6%) or 12 (1.5%). The remainder of GISTs (12%) were wild type for both KIT and PDGFRA. Comparative studies of KIT-mutant, PDGFRA-mutant, and wild-type GISTs indicate that there are many similarities between these groups of tumors but also important differences. In particular, the responsiveness of GISTs to treatment with the kinase inhibitor imatinib varies substantially depending on the exonic location of the KIT or PDGFRA mutation. Given these differences, which have implications both for the diagnosis and treatment of GISTs, we propose a molecular-based classification of GIST. Recent studies of familial GIST, pediatric GIST, and variant forms of GIST related to Carney's triad and neurofibromatosis type 1 are discussed in relationship to this molecular classification. In addition, the role of mutation screening in KIT and PDGFRA as a diagnostic and prognostic aid is emphasized in this review.
Insights
Gastrointestinal stromal tumors (GISTs) are linked to KIT or PDGFRA gene mutations. Mutation type impacts imatinib treatment response, supporting a molecular classification for GIST diagnosis and therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastrointestinal stromal tumors (GISTs) were historically ill-defined but are now recognized as a distinct oncogenetic entity.
- GISTs serve as a model for studying oncogenic kinase mutations in human tumorigenesis.
- Kinase-targeted therapies are central to GIST clinical trials.
Purpose of the Study:
- To review the progress in understanding GIST oncogenetics.
- To analyze the frequency and impact of KIT and PDGFRA mutations in GIST.
- To propose a molecular-based classification for GIST.
Main Methods:
- Review of existing literature on GIST oncogenesis and targeted therapies.
- Detailed analysis of mutations in the KIT and PDGFRA genes in 322 GIST cases.
- Comparative studies of GIST subtypes based on mutation status.
Main Results:
- Approximately 80-85% of GISTs harbor activating KIT mutations (exons 11, 9, 13, 17).
- PDGFRA mutations were found in a subset of GISTs (exons 18, 12).
- 12% of GISTs were wild type for both KIT and PDGFRA.
- GIST responsiveness to imatinib varies significantly based on specific KIT/PDGFRA mutation location.
Conclusions:
- A molecular-based classification of GIST is proposed, integrating genetic findings.
- Mutation screening of KIT and PDGFRA is crucial for GIST diagnosis and prognosis.
- Understanding specific mutations aids in tailoring imatinib therapy for GIST patients.
