PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Corless
Christopher L
CL
Department of Pathology, Division of Hematology and Oncology, Oregon Health & Science University Cancer Institute, Portland, OR 97201, USA.
Schroeder
Arin
A
Griffith
Diana
D
Town
Ajia
A
McGreevey
Laura
L
Harrell
Patina
P
Shiraga
Sharon
S
Bainbridge
Troy
T
Morich
Jason
J
Heinrich
Michael C
MC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D016466:CHO Cells; D006224:Cricetinae; D019008:Drug Resistance, Neoplasm; D005091:Exons; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D020033:Protein Isoforms; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D014162:Transfection
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D020033:Protein Isoforms; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha