PDGFRA mutations in gastrointestinal stromal tumors: Frequency, spectrum and in vitro sensitivity to imatinib

被引:639
作者
Corless, CL
Schroeder, A
Griffith, D
Town, A
McGreevey, L
Harrell, P
Shiraga, S
Bainbridge, T
Morich, J
Heinrich, MC
机构
[1] Oregon Hlth & Sci Univ, Inst Canc, Dept Pathol, Portland, OR USA
[2] Oregon Hlth & Sci Univ, Inst Canc, Div Hematol & Oncol, Portland, OR USA
[3] Portland VA Med Ctr, Portland, OR USA
关键词
D O I
10.1200/JCO.2005.14.068
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 There were 80 tumors (7.2%) with a PDGFRA mutation: 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, D1842-8431M) 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.
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页码:5357 / 5364
页数:8
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