Molecular cytology genotyping of primary and metastatic GI stromal tumors by using a custom two-gene targeted next-generation sequencing panel with therapeutic intent
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Updated: Mar 22, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Ferga C Gleeson1, Sarah E Kerr2, Benjamin R Kipp2
1Divison of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
Background And Aims:
In an era of precision medicine, customized genotyping of GI stromal tumors by screening for driver mutations will become the standard of care. The fidelity of genotype concordance between paired cytology smears and surgical pathology specimens is unknown. In patients with either primary or metastatic sporadic disease, we sought to determine the frequency of KIT and PDGFRA pathogenic alterations within such specimens, imatinib sensitivity, and the concordance of pathogenic alterations between paired specimens.
Methods:
DNA obtained from cytology smears from 36 patients, 24 of whom had paired surgical pathology specimens, underwent targeted next-generation sequencing by using a custom panel to evaluate somatic mutations within KIT (exon 2, 9, 10, 11, 13, 14, 15, 17, 18) and PDGFRA (exon 12, 14, 15, 18) genes. Patients with KIT and PDGRFA wild-type genes completed the Qiagen Human Comprehensive Cancer GeneRead DNAseq Targeted Array V2.
Results:
Genotyping revealed KIT and PDGFRA mutations in 68% and 15% of patients. The wild-type population did not harbor mutations in BRAF, RAS family, SDHB, SETD2, or NF1. Imatinib sensitivity based on the oncogenic kinase mutation prevalence was estimated to be 68%. Mutational concordance between paired cytology and surgical pathology specimens was 96%.
Conclusions:
Our data have demonstrated the ability to stratify either primary or metastatic gastrointestinal stromal tumors by mutational subtype using a targeted next-generation sequencing 2 gene mutation panel. We highlight the ability to use cytology specimens obtained via minimally invasive techniques as a surrogate to surgical specimens given the high mutational landscape concordance between paired specimens.
Insights
Cytology smears accurately identify KIT and PDGFRA mutations in gastrointestinal stromal tumors (GIST), showing high concordance with surgical specimens. This supports using minimally invasive cytology for precise GIST genotyping and treatment selection.
Area of Science:
- Oncology
- Genetics
- Precision Medicine
Background:
- Gastrointestinal stromal tumors (GIST) require precise genotyping for targeted therapy.
- The concordance of genetic mutations between cytology and surgical pathology in GIST is not well-established.
- Precision medicine necessitates reliable methods for identifying driver mutations.
Purpose of the Study:
- To determine the frequency of KIT and PDGFRA mutations in GIST specimens.
- To assess imatinib sensitivity based on identified mutations.
- To evaluate the genotype concordance between paired cytology and surgical pathology specimens.
Main Methods:
- Targeted next-generation sequencing of KIT and PDGFRA genes in DNA from cytology smears.
- Analysis of 36 patients, including 24 with paired surgical pathology specimens.
- Evaluation of mutations in specific exons of KIT and PDGFRA.
Main Results:
- KIT and PDGFRA mutations were found in 68% and 15% of patients, respectively.
- Estimated imatinib sensitivity was 68% based on mutation prevalence.
- High mutational concordance (96%) was observed between paired cytology and surgical pathology specimens.
Conclusions:
- Targeted sequencing of cytology specimens can effectively stratify GIST by mutational subtype.
- Minimally invasive cytology specimens serve as reliable surrogates for surgical specimens in GIST genotyping.
- This approach supports the standard of care for precision medicine in GIST.
