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PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib
Christopher L Corless1, Arin Schroeder, Diana Griffith
1Department of Pathology, Division of Hematology and Oncology, Oregon Health & Science University Cancer Institute, Portland, OR 97201, USA.
Purpose:
Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs.
Materials And Methods:
We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing.
Results:
66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings.
Conclusion:
Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.
Insights
Gastrointestinal stromal tumors (GISTs) with PDGFRA mutations show varied responses to imatinib. Some mutations are sensitive, suggesting mutation screening aids GIST treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastrointestinal stromal tumors (GISTs) often have KIT mutations, targeted by imatinib.
- A subset of GISTs harbors platelet-derived growth factor receptor alpha (PDGFRA) mutations, with some conferring imatinib resistance.
Purpose of the Study:
- To investigate the spectrum of PDGFRA mutations in GISTs.
- To determine the in vitro sensitivity of various PDGFRA mutations to imatinib.
Main Methods:
- Analysis of KIT and PDGFRA mutation status in 1,105 GISTs.
- Utilized denaturing high-performance liquid chromatography and direct sequencing.
- Assessed imatinib sensitivity of PDGFRA mutant isoforms via cell line expression studies.
Main Results:
- Identified 66 PDGFRA mutations in exon 18, 11 in exon 12, and three in exon 14.
- Exon 12 mutations and N659K in exon 14 were imatinib sensitive.
- Most D842 substitutions in exon 18 were imatinib resistant, except D842Y; other exon 18 mutations were sensitive.
Conclusions:
- Over one-third of PDGFRA-mutant GISTs may respond to imatinib.
- The D842V mutation is the most common imatinib-resistant PDGFRA mutation (62.6%).
- PDGFRA mutation screening can inform GIST management strategies.
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